0163-769X/91/1201-0045$03.00/0
Endocrine Reviews
Copyright © 1991 by The Endocrine Society
Vol. 12, No. 1
Printed in U.S.A.
Cell-Cell Interactions in the Testis*
MICHAEL K. SKINNERf
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6600
genesis, organogenesis, and determination of cell lineage
(reviews in Refs. 8-12). Alterations in these cell-cell
interactions, therefore, may cause abnormal tissue physiology associated with disease states. Disorganization of
normal cell-cell and cell-basement membrane interactions is associated with the process of metastasis and
malignancy (13-16). Alterations in cellular differentiation associated with cell-cell interactions will also result
in abnormal tissue functions (17, 18). Further examination of the cellular and molecular biology of abnormal
tissue physiology is speculated to reveal that many cellular oncogenes (19) and tumor suppressor genes (20)
may be associated with cell-cell interactions (21).
The increasing awareness of the importance of cellcell interactions has become critical in disciplines such
as endocrinology, cell biology, and pharmacology. This
is illustrated in the more than 700 literature citations
during the past year on the topic of cell-cell interactions.
The cellular interactions identified have also increased
dramatically in diversity. A categorization of cell-cell
interactions is proposed to help classify the different
types of interactions as well as understand the interrelationships between the different interactions in the
control of tissue function (Table 1 and Ref. 22). Cellular
interactions are classified into three general categories
of environmental, nutritional, and regulatory interactions. The categorization of cell-cell interactions presented provides a vocabulary with which to distinguish
the various types of interactions as well as classify the
effects of specific interactions on cellular physiology. The
classification of cell-cell interactions (22) shown in Table
1 will be used to more thoroughly discuss the specific
cell-cell interactions in the testis.
I. Introduction
A. Concept and categorization of cell-cell interactions
B. Testis cell biology and function
C. Analysis of cell-cell interactions
II. Specific Cell-Cell Interactions
A. Sertoli cell-germinal cell interactions
B. Peritubular cell-Sertoli cell interactions
C. Sertoli cell-Leydig cell interactions
D. Leydig cell-peritubular cell interactions
E. Additional cell-cell interactions
III. Summary
A. Testicular cell-cell interactions
B. Endocrine regulation of testis function
C. Future directions
I. Introduction
A. Concept and categorization of cell-cell interactions
T
HE ability of cells to interact and communicate is
a biological phenomenon that developed with the
evolution of multicellular organisms. The cell-cell interactions that have evolved are essential for the survival
of both simple organisms such as dictyostelium and
complex organisms such as mammals. These cellular
associations allow an organism to develop capacities that
are greater than the simple sum of their individual parts.
As early as 1878, Claude Bernard proposed that the
"milieu in.terieur" (i.e. internally produced fluid environment) and a cybernetic-like control system (i.e. cell-cell
interactions and communication) in multicellular organisms are needed to adaptively regulate the growth,
development, and maintenance of normal tissue function
(1, 2). The experimental analysis of cellular interactions
was initiated with the investigation of cell aggregation in
simple organisms such as sponges (3, 4) and progressed
into the areas of embryology (5) and cell biology (6, 7).
Analysis of cell biology on a molecular level has revealed
the importance of cell-cell interactions during embryo-
B. Testis cell biology and function
The observation that early man domesticated animals
through castration implies that the testis is likely one of
the first organs investigated on a physiological level.
This is supported by reference to the testis in ancient
Greek, Roman, Egyptian, and Assyrian writings (23-26).
Scientists engaged in the developing discipline of
anatomy retained this interest in reproduction and
Address requests for reprints to: Dr. Michael K. Skinner, Department of Pharmacology, Vanderbilt University School of Medicine,
Nashville, Tennessee 37232-6600.
* Experiments presented in this paper were supported in part by
NIH Grant HD-20583.
f
PEW Scholar.
45
SKINNER
46
TABLE 1. Categorization of cell-cell interactions
Classification
Definition
Examples/mediators
Environmental
Interactions that influence the extracellular environment of the cell to
affect cell contacts
and cytoarchitecture
Extracellular matrix:
cell adhesion molecules
Nutritional
Interactions involved
in the delivery of
essential nutrients
between cells
Transfer of energy
metabolites, metals, or vitamins
Regulatory
Agents provided by a
cell that through a
signal transduction
event regulates another cell's function on a molecular level
Paracrine/autocrine
factors: growth
factors; differentiation factors; cytokines
investigated the details of testis and sperm cell structure,
which played a role in the development of the cell theory
(27-30). The advent of the light microscope facilitated
anatomical analysis of the testis with often surprising
detail (31-33). More recently, investigators (34-39) have
explored the ultrastructure of the testis by means of the
electron microscope. Comparative anatomy of the testis
of a number of species indicates that although differences
can be observed, the process of spermatogenesis and
cellular associations are similar in many animals (40,
41).
In most mammals the process of spermatogenesis occurs within seminiferous tubules that release spermato-
Vol. 12, No. 1
zoa into a rete testis which is connected to the epididymis
(Fig. 1). The seminiferous tubules are formed by the
Sertoli cells that provide structural support for the developing germinal cells. Peritubular myoid cells surround
the tubule and are in contact with the basal surface of
the Sertoli cells. In the interstitium of the testis between
tubules are the Leydig cells responsible for the production of androgen. The majority of research on the cell
biology of the testis has focused on Sertoli, peritubular
myoid, Leydig and/or developing germinal cells. Cell-cell
interactions between all three of the somatic cells are
possible; however, Sertoli cells appear to be the primary
somatic cell to directly interact with the developing
germinal cells. The cellular associations and interactions
illustrated in Fig. 2 will be reviewed.
In addition to investigation of the anatomy of the
testis, the observation of Smith in 1930 that removal of
the pituitary inhibited the process of spermatogenesis
(42, 43) initiated an intense investigation of the endocrine regulation of testis function that continues today
(44, 45). Initial speculation was that hormones acted
directly on germinal cells (46-49). Subsequent research
and consideration of testis physiology, however, demonstrated that the actions of hormones are primarily confined to the somatic cells (review in Refs. 50 and 51).
The appreciation that the endocrine hormones, particularly androgens, acted directly on the somatic cells of the
testis, and not the germinal cells, led to initial speculations reviewed by Fritz in 1978 (50) regarding the potential importance of cell-cell interactions in the endocrine
regulation of testis function.
Recent studies have identified numerous secretory
products of specific testicular cell types. These products
range from steroids to specific secreted proteins. Inter-
Seminiferous Tubules
Leydig
^ ~ ^ L Peritubular
Sertoli
Testis
FIG. 1. Cell biology of the testis.
CELL-CELL INTERACTIONS IN THE TESTIS
February, 1991
47
TABLE 2. Major Sertoli cell secretory products
Peritubulor
Secretory product
Transport/binding
proteins
ABP (60-62)
Transferrin (63)
Ceruloplasmin (64)
Sulfated glycoprotein-1 (65-67)
Function and/or
characteristics
Androgen transport/localization
Iron transport
Copper transport
Sphingolipid binding (68)
Germinal
FIG. 2. Cell-cell interactions in the testis.
estingly, most of the secretory products identified appear
to be involved directly or indirectly in cell-cell interactions. For this reason, the major secretory products of
Sertoli cells, Leydig cells, and peritubular cells will be
categorized and tabulated for subsequent reference.
The secretory products of Sertoli cells and their proposed functions have previously been reviewed (37, 50,
52-59). The major Sertoli cell products (60-102) are
shown in Table 2 and include transport/binding proteins,
proteases, extracellular matrix components, growth factors, and cellular metabolites. These Sertoli cell secretory
products will subsequently be discussed in reference to
specific cell-cell interactions.
The critical secretory role of the Leydig cell was established with the early observations that Leydig cells are
the primary site of androgen production (103,104) which
is under endocrine control (reviews in Ref. 105-107) and
essential for the maintenance of spermatogenesis and
the endocrine status of the male. Nonsteroidal Leydig
cell secretory products have not been thoroughly investigated. Although few secretory products have been identified and/or characterized, the major secretory products
known (Table 3) appear to be involved in cell-cell interactions.
The peritubular myoid cell has also recently been
shown to secrete components that may be important for
the maintenance and control of testicular function. As
found with Sertoli cells and Leydig cells, the secretory
products of peritubular cells identified (Table 3) also
appear to be involved in cell-cell interactions.
Proteases/inhibitors
Plasminogen activator (72, 73)
Cyclic protein-2
(75-76)
a2-Macroglobulin
(78)
Extracellular matrix
components
Laminin (79)
Collagen IV and I
(79)
Proteoglycans (80)
Growth factors
TGFa (81)
TGF/3 (82)
IGF-I (83-86)
IL-1 (88)
Regulatory proteins
Inhibin (93)
Mullerian duct inhibitory agent
(94)
Sulfated glycoprotein-2 (95, 96)
Metabolites
Lactate/pyruvate
(89-91)
Estrogen (92)
Potential correlates
S70 (69)
Band 4 (70)
Testibumin (71)
Activate plasminogen (74)
Cathepsin activity
(77)
Protease inhibitor
Extracellular matrix
component
Extracellular matrix
component
Extracellular matrix
component
Growth stimulation
Growth inhibition
Maintenance
growth/differentiation
Growth regulation
SC-EGF (87)
Endocrine/paracrine agent
Fetal Sertoli cells
development
Sperm coating (66) DAG-protein (65-66)
Immunosuppressant Clusterin (99-101)
(97, 98)
S45:S35 (69)
CMB-21 (102)
Energy metabolites
Steroid hormone
C. Analysis of cell-cell interactions
A number of different experimental approaches can be
taken to investigate cellular interactions and identify
potential autocrine and paracrine agents (Table 4). A
thorough examination requires a number of criteria to
be considered including localization, production, secretion, characterization, action, and physiology. Few testicular cell interactions examined have considered all the
criteria listed in Table 4. Therefore, examination of cellcell interactions in the testis requires a critical consideration of the data available to determine which cellular
interactions are simply speculated to exist us. those more
thoroughly established as important physiologically.
As demonstrated with many organs and tissues (121—
123), the advent of cell culture procedures has provided
48
SKINNER
TABLE 3. Major Leydig cell and peritubular cell secretory products
Function and/or
characteristic
Secretory product
Leydig cells:
Androgen (103, 104)
POMC peptides (108-112)
Inhibin (113)
IGF-I (114)
Peritubular cells:
PModS (117-119)
Plasminogen activator inhibitor (120)
Fibronectin (115-116)
Collagen I (79)
Proteoglycans (80)
TGFa (81)
TGF|3 (82)
IGF-I (114)
Steroid/endocrine/paracrine
agent
Opiods/POMC regulatory
agents
Endocrine/paracrine regulatory agents
Maintenance growth/differentiation
Paracrine regulatory agent
Inhibition of plasminogen activator activity
Extracellular matrix component
Extracellular matrix component
Extracellular matrix component
Growth stimulation/EGF-like
Growth inhibition
Maintenance growth/differentiation
a significant advance in an understanding of the molecular and cellular aspects of testis function. Initially organ
culture of the testis was utilized (124-126); however,
individual cell types were subsequently isolated and cultured to provide more definitive information regarding
their functions and hormone responses. Methods have
been developed to isolate purified preparations of Leydig
cells (127-134), germinal cell populations at various
stages of development (135-146), Sertoli cell populations
(147-160), and peritubular myoid cells (161-165). Histochemical and immunocytochemical procedures have
been developed to assess the purity of cell preparations
(161, 162, 165, 166). Several cell lines have been developed for Sertoli cells and Leydig cells (167-169) which
TABLE 4. Considerations for potential agents involved in cell-cell interactions
Criteria
Localization
Production
Secretion
Characterization
Action
Physiology
Method
Immunohistochemistry
Gene expression/protein synthesis
Presence in conditioned medium/biological fluids
Protein structure/purification
RNA/DNA sequence
Bioactivity/pharmacology
In vivo analysis
Observations/
information
Presence of agent
Local site production
Extracellular actions/soluble agent
Novelty of agent
Site action/function
Function/relevance
Vol. 12, No. 1
are useful for investigation of parameters such as signal transduction events or when a product of interest is
produced by the cells. The majority of experiments regarding cell-cell interactions in the testis have used primary cell cultures.
When an in vitro experimental approach is utilized it
is inevitable and appropriate that questions regarding
physiological relevance be raised (170). Eagle (171) provided insight early in the establishment of in vitro cell
culture procedures when he stated "the study of discrete
cells will not suffice to explain the interaction of many
different cell types associated into organs which in turn
exercise a mutual control." Therefore, a combination of
an in vitro analysis to investigate molecular parameters
and an in vivo analysis to investigate physiological parameters will be most useful to elucidate cell-cell interactions.
II. Specific Cell-Cell Interactions
Consideration of cell-cell interactions in the testis
began with the identification of multiple testicular cell
types which initiated studies that have continued for the
past 100 yr. The increased amount of research in the
area of cellular interactions in the testis over the past 20
yr can be illustrated by the number of literature citations
obtained from a National Library of Medicine literature
search on the general topic of cell-cell interaction in the
testis (Fig. 3). A significant and continuous rise in the
number of citations per year is apparent. For this reason
there have been a number of informative reviews (22, 50,
51, 172-191) that address selected cellular interactions,
individual agents involved in specific cellular interactions, or the research associated with a given laboratory.
A. Sertoli cell-germinal cell interactions
The early microscopic examination of spermatogenesis
and the development of the spermatozoa within the
seminiferous tubules were active areas of research between 1830 and 1860 (192). Although the concept of a
support cell for the developing germinal cells was discussed, this idea was not seriously considered by figures
such as Koelliker who suggested the presence of polygonal cells as a paved epithelium. In 1865, however, Enrico
Sertoli (193) described the existence of special branched
cells in the seminiferous tubules of the human testis.
Sertoli postulated "the function of the branched cells is
linked to the formation of spermatozoa." Further analysis of the Sertoli cell and its association with the developing germinal cells led to the concept reviewed by Peter
in 1899 (31) that this "nurse cell" is essential for the
germinal cell and the process of spermatogenesis. The
research that has progressed since that time has refined
these observations and provided insight into the molec-
February, 1991
CELL-CELL I
CELL-CELL TESTIS CITATIONS
60
|
o>
50
/
/
40 -
o
/
£ 30
»—
« 2° •
UJ
/
CQ
|
10
0
0
70
75
80 85
YEAR
90
FIG. 3. Number of citations per year derived from a National Library
of Medicine literature search on the topic of cell-cell interactions in
the testis.
ular mechanisms that Sertoli cells utilize to influence
germinal cell development.
Environmental. The cytoarchitectural arrangements between Sertoli cells and the developing germinal cells
provide one of the most complex examples of an environmental cell-cell interaction. The columnar and convoluted structure of the Sertoli cells, which extends from
the basal to the apical surface of the seminiferous tubule
(review in Ref. 37), provides the physical support for the
spermatogonia undergoing mitosis, the spermatocytes
undergoing meiosis, and the spermatids undergoing the
process of spermiogenesis to become spermatozoa (reviews in Refs. 194-196). The Sertoli cell is also required
to maintain the germ cell syncitium that connects all the
cells derived from an initial clone of cells. One of the
initial environmental interactions postulated to be important was identified between Sertoli cells near the base
of the epithelium as tight and gap junctions referred to
as junctional specializations (197-199). These tight junctions were found to exclude the passage of macromolecules from the interstitial space to the lumen of the
seminiferous tubules (200-202). These observations provided support for the existence of a blood-testis barrier
initially postulated from an examination of the ionic,
amino acid, and protein content of testicular fluids from
the tubule, lymph, and plasma (203-206). The environmental interactions between Sertoli cells mediated by
this tight junction, therefore, are essential in the creation
of the blood-testis barrier and the maintenance of the
unique microenvironment within the seminiferous tubule
required for germinal cell development (207).
Specific types of environmental interaction identified
between Sertoli cells and germinal cells include the ec-
49
toplasmic specializations (208-210). These are flattened
cisternae of the Sertoli cell endoplasmic reticulum that
appear in Sertoli cell membranes facing spermatocytes
and the acrosomes of the spermatids (197-199, 211-214).
These junctional specializations have generally been considered attachment devices (198,199, 208, 215). Another
specific environmental interaction identified between
Sertoli cells and germinal cells is referred to as the
tubulobulbar complex (209, 216, 217). This is a narrow
tubular projection of plasma membrane from the heads
of maturation-phase spermatids that invaginate the adjacent plasma membrane of Sertoli cells (218, 219). The
functional significance of these structures remains to be
determined (220).
In an elegant set of experiments designed to investigate
the complexity of the structural interactions between
Sertoli cells and germinal cells, a three-dimensional
structure of an individual Sertoli cell was determined
(212, 221, 222). These studies of Russell and colleagues
demonstrated that an individual Sertoli cell can be in
contact with 5 adjacent Sertoli cells at the basal surface
of the cell and 47 adjacent germinal cells at various
stages of development. The morphology of the Sertoli
cell, therefore, is exceedingly complex, and the ability of
an individual cell to be in contact with greater than 50
adjacent cells indicates the importance of environmental
interactions between the cells.
The presence of various generations of spermatocytes
and spermatids derived from individual spermatogonia
(223) initiates waves of spermatogenesis that are not
random but instead occur in a specific cyclic manner
referred to as stages (224). Progression of these stages of
germinal cells is referred to as the cycle of the seminiferous epithelium and suggests potential alterations in
cellular function during this cycle (187, 224-228).
Changes that occur in Sertoli cell size (229, 230) and
lipid content (225, 231, 232) during the cycle have been
examined. Transillumination procedures to microdissect
different stages have been developed (233, 234) and used
to investigate biochemical aspects of the cycle (review in
Ref. 187). Comparison of stages in rodents us. humans
(235) implies that the dynamics of the cycle can vary
between species. Experiments recently designed to manipulate the cycle of the seminiferous tubule were based
on the dependence of spermatogenesis on retinoids (236239). Vitamin A deficiency causes an arrest at the preleptotene stage of spermatogenesis (238, 240). Morales
and Griswold (241) found that replacement of vitamin A
to deficient animals restores spermatogenesis in a synchronized stage-specific manner. All the seminiferous
tubules in a synchronized testis appear to be at the same
stage of the cycle, which provides a technical advance to
study the cycle of the seminiferous epithelium as well as
50
SKINNER
environmental interactions between the Sertoli cells and
germinal cells (241-243).
The continuous nature of germinal cell development
and the presence of the cycle of the seminiferous epithelium indicate that environmental interactions between
Sertoli cells and germ cells are dynamic and will require
a rapid rate of tissue remodeling. The initial aspect of
tubule remodeling considered was the need to translocate
early stage spermatocytes from the basal compartment
to the apical compartment through the tight junctional
complex (244-248). The production of plasminogen activator and other protease activities by Sertoli cells (72,
77, 249) may be needed in several aspects of tissue
remodeling associated with translocation of spermatocytes, degradation of junction complexes, and release of
mature spermatozoa into the lumen of the tubule. The
function and control of the proteolytic activities in the
tubule requires further investigation.
The presence of junctional contacts between Sertoli
cells and germinal cells observed microscopically suggested that these environmental interactions may be
needed for cell attachment and association (250, 251).
Germinal cell shape and junctional interactions can be
maintained in vitro (252), and the viability of spermatogenic cells is facilitated by coculture with Sertoli cells
(253). The binding of germ cells to Sertoli cells is specific
and temperature dependent (254). Proteins on the surface of spermatogenic cells potentially involved in the
environmental interaction with Sertoli cells have been
identified (255, 256), and specific Sertoli cell-secreted
proteins have also been speculated to be involved in this
attachment process (257). Sertoli cells also must adhere
firmly to the membrane of the residual bodies of released
spermatozoa to prevent their loss from the surface of the
seminiferous epithelium (215). These residual bodies
must be freed from the released spermatozoa, remain
attached to the Sertoli cells (209, 258), and subsequently
be phagocytized and metabolized by the Sertoli cells (227,
259).
Nutritional. The transport of essential nutritional components between Sertoli cells and germinal cells is critical
for germ cell survival and metabolism. The earliest reference to the Sertoli cell was with regard to its probable
"nurse cell" function for the developing spermatogenic
cells (31, 193). A number of Sertoli cell functions have
been identified on a molecular level that are directly or
indirectly involved in the nutritional support of the
germinal cells. These nutritional interactions between
Sertoli cells and germinal cells are required due to the
presence of the blood-testis barrier (207, 260, 261). One
of the major functions of the Sertoli cells that has evolved
is the ability to transport essential nutritional compo-
Vol. 12, No. 1
nents to the spermatogenic cells sequestered in a serumfree unique microenvironment.
Early during fetal development, junctional interactions
between the germ cells and immature Sertoli cells may
facilitate transfer of nutritional agents between the cells
(262-265). In the adult testis a complex interaction,
referred to as a desmosome-gap junction, forms between
Sertoli cells and germ cells (198, 212, 263, 266, 267).
These junctions appear to form primarily between Sertoli
cells and pachytene spermatocytes and are less frequent
with spermatids (212). These junctional complexes are
permeable to agents with mol wt less than 600-700 (263)
and appear to transfer metabolic substances such as
choline between Sertoli cells and germ cells (268). Due
to the existence of the germ cell syncitium and cytoplasmic bridges between germinal cells, junctional contacts may not be necessary between each spermatogenic
cell and Sertoli cell. Further examination of the functional importance and the components transported by
gap junctions between the Sertoli cells and germinal cells
is required.
Developing spermatogenic cells sequestered within the
blood-testes barrier are not exposed to the high glucose
levels in the interstitial fluid. Localization of metabolic
enzymes such as ATPase in the tubule (269) and demonstration that Sertoli cells produce glucose metabolites
such as inositol (270) suggested that Sertoli cells may
provide energy metabolites to germinal cells. Sertoli cells
have been shown to metabolize glucose to lactate and
pyruvate resulting in high levels of extracellular metabolites (89-91, 271) that increase in response to FSH (90,
91, 272-274). Both pyruvate and lactate were found to
support germinal cell metabolism and appear to provide
an efficient energy source for the cells (90, 91, 272, 275277). Analysis of metabolic enzymes, such as lactate and
malate dehydrogenases (278), and the actions of FSH on
glucose transport by Sertoli cells (279) also suggest that
Sertoli cells may provide energy metabolites to spermatogenic cells. Whether the lactate and pyruvate can be
transported by gap junctions between the cells or by
active transport across the plasma membranes remains
to be determined. Although the physiological significance
of pyruvate and lactate production by Sertoli cells remains to be elucidated, the sequestration of the developing germinal cells within the blood-testis barrier suggests that the Sertoli cells will likely be required to
provide an energy source for spermatogenic cells. Other
cellular metabolites, such as coenzymes, nucleotides, and
amino acids, may also require a nutritional interaction
between these cells to support the process of spermatogenesis.
Although many nutritional components are small soluble molecules that can be transported by junctional
interactions or secreted, a large number of substances
February, 1991
CELL-CELL INTERACTIONS IN THE TESTIS
FlG. 4. Binding protein-mediated nutritional interaction between Sertoli cells and germinal cells in the seminiferous tubule. Serum-derived
binding protein (sBP) with a nutritional component (*) bound (BP-*)
and transfer with a Sertoli cell-derived testicular binding protein (tBP).
require binding proteins to facilitate transport due to low
solubility or reactive chemical properties. Functional
identification of Sertoli cell-secreted proteins has revealed the production of a number of different transport
proteins (reviews in Refs. 53-56). The Sertoli cells appear
to acquire essential nutritional components at the basal
surface of the cell from specific binding proteins present
in the interstitial fluid. The serum binding proteins can
enter the cell and transfer the nutritional component to
a newly synthesized binding protein. The testicular binding protein can then be secreted by the Sertoli cell and
transport the nutritional component to developing germinal cells sequestered within the blood-testis barrier
(Fig. 4). The first Sertoli cell transport protein identified
was androgen binding protein (ABP) (Refs. 60+62; review
Ref. 53). Although ABP is a useful marker of Sertoli cell
function (280), the transport of androgen to germinal
cells is not required (50). The postulated function for
ABP is to localize the transport androgens throughout
the male reproductive tract; therefore, ABP does not
appear to mediate a nutritional interaction between Sertoli cells and germinal cells. An abundant Sertoli cell
secretory product functionally identified is testicular
transferrin (63). Transferrin is an iron-binding protein,
previously thought to be primarily produced by the liver,
that binds and transports iron in the circulatory system.
Iron is bound by transferrin with an extremely high
affinity due to the low solubility of iron. All cells require
51
iron for cytochrome activity and respiration (281). The
transferrin produced by Sertoli cells is the same gene
product as serum transferrin produced by the liver with
differences in glycosylation of the two proteins (282,
283). Transferrin delivers iron to the cell through a
receptor-mediated process. Transferrin and the receptor
complex are endocytosed to an acidified vesicle where
iron is released, and the transferrin and receptor complex
is recycled to the cell surface (284, 285). Transferrin
receptors are present on all cells, and high concentrations
of transferrin receptors have been localized on pachytene
spermatocytes (286, 287). The observations from a number of laboratories support this proposed transferrinmediated nutritional interaction between Sertoli cells
and germinal cells (63, 287-292). Another metal binding
and transport protein found to be synthesized and secreted by Sertoli cells is ceruloplasmin (64). Ceruloplasmin is a copper transport protein, also thought to be
primarily produced by the liver, that binds and transports
copper to cells that require copper as a coenzyme for
proteins and feroxidase (293, 294). A nutritional interaction is proposed for ceruloplasmin that is similar to
transferrin with the exception that the ceruloplasmin
receptor complex appears to be degraded upon internalization. The nutritional interaction between Sertoli cells
and germinal cells involving ceruloplasmin is not as
thoroughly characterized as the nutritional interaction
mediated by transferrin.
Lipids are another nutritional component that generally require a binding protein for transport. Several
unique fatty acids have been identified in Sertoli cells
and germinal cells, and the potential transport of these
fatty acids from Sertoli cells to germinal cells has been
postulated (295, 296). Although the production of general
lipid transport proteins by Sertoli cells has not been
thoroughly investigated, one specific lipid binding protein has been identified. A major Sertoli cell-secreted
protein referred to as sulfated glycoprotein-1 (SGP-1)
(66, 67) has been identified as a unique form of a sphingolipid-binding protein involved in sphingolipid solubilization (67, 68). The precursor form of sphingolipid activator protein that is involved in sphingolipid binding
and metabolism (68) has been shown to have a high
degree of homology with SGP-1 (67, 68). The lipid specificity of SGP-1 is unclear, and the possibility that SGP1 may be involved in more general lipid binding remains
to be investigated. The rapid expansion of the germ cell
population during spermatogenesis is anticipated to require the transport of lipid precursors and specific fatty
acids between Sertoli cells and germinal cells (295). In
addition, the metabolism and degradation of the residual
body by Sertoli cells are also anticipated to require lipidbinding proteins. Further investigation of lipid transport
and the binding proteins involved is required.
SKINNER
52
Sertoli cells will also likely have developed a mechanism with which to transport vitamins to spermatogenic
cells. Many vitamins utilize binding proteins in the circulatory system to facilitate their transport and localization. Preliminary evidence exists for the production of
vitamin-binding proteins by Sertoli cells, such as folatebinding protein and biotin-binding protein, that may
transport these vitamins to germinal cells (296). Further
characterization and investigation of potential Sertoli
cell derived vitamin-binding proteins are required. As
discussed previously, one vitamin that has been shown
to be essential for testis function and spermatogenesis is
vitamin A, retinoids (236-239, 298). Cellular retinoidbinding proteins have been localized in Sertoli cells
(299-301) and germinal cells (300, 302). Sertoli cells
respond directly to retinol and retinoic acid with an
increase in several functional parameters (303-307), including transferrin production (Fig. 5). Vitamin A deficiency also directly influences Sertoli cell functions (SOSSI 1). Retinoids appear to act on Sertoli cells through the
nuclear retinoid receptor to directly regulate Sertoli cell
functions. Information regarding the actions of vitamin
A on spermatogenesis, however, imply that retinoids also
directly influence germ cell development (236-243, 312).
Due to the low solubility of retinoids, binding proteins
in the serum, retinol-binding protein, and the cell, cellular retinol and retinoic acid binding proteins exist to
facilitate retinoid transport. The majority of retinol accumulation by Sertoli cells is esterified with lipids and
apparently stored as compounds such as retinol-palmitate esters (313, 314). Retinol-binding protein facilitates
the uptake of retinol by Sertoli cells (315) and whether
retinol, retinoic acid and/or retinol-esters are transported to germinal cells remains to be investigated. Although several studies have implied that Sertoli cells
TRANSFERRIN PRODUCTION BY SERTOLI CELLS
.5 8 0 -
F
I
R
T
TREATMENT
FIRT PMODS
FIG. 5. Transferrin production by Sertoli cells isolated from 20 dayold rats and cultured for 5 days in the absence, control (C), or presence
of 100 ng/ml FSH (F), 5 Mg/ml insulin (I), 0.35 fiU retinol (R), 1 fiM
testosterone (T), a combination of FSH, insulin, retinol, and testosterone (FIRT), or 20 ng/ml PModS (PMODS). Transferrin levels were
determined with a RIA and expressed as (nanograms per ^g Sertoli cell
DNA) and presented as the mean ± SEM of three different experiments
performed in triplicate.
Vol. 12, No. 1
may be capable of producing a retinoid binding protein
(316, 317), the detection and characterization of a Sertoli
cell-derived retinoid binding protein that may facilitate retinoid transport to germinal cells remain to be
elucidated.
Regulatory. Regulatory interactions between Sertoli cells
and germinal cells were proposed as the concepts of
paracrine factors and local trophic agents developed.
Initial morphological observations regarding alterations
of Sertoli cell-germinal cell associations led several laboratories to postulate the potential presence of such
interactions. Disruption of testis cell associations and
morphology by heat (318), irradiation (319-321), cytotoxic agents (322), or disease states (323) suggested that
regulatory interactions may exist between Sertoli cells
and germinal cells. Analysis of the expression of specific
genes in germ cells and Sertoli cells at different stages of
the seminiferous cycle (324) and the effects of removal
of germ cells on Sertoli cell products in vivo also suggested that germ cells may regulate Sertoli cell function
(325, 326). In addition, the ability of hormones to indirectly influence germinal cell development through actions on the Sertoli cells supports the presence of interactions between the cells (50, 327, 328). Although these
experiments and observations imply that interactions
appear to occur between Sertoli cells and germinal cells,
the specific type of interaction involved can not be distinguished. As previously discussed, alterations in critical
environmental or nutritional interactions may have profound effects on spermatogenic cells and Sertoli cells.
Further investigation of potential regulatory interactions
between Sertoli cells and germinal cells requires the
elucidation of the paracrine factors involved.
Initial experiments to investigate the effects of Sertoli
cells on germinal cells utilized coculture of the cells. The
presence of Sertoli cells in culture with spermatogenic
cells has been shown to stimulate germ cell RNA and
DNA synthesis (329), induce the appearance of germ cell
surface antigens (330), and maintain spermatogenic cell
glutathione synthesis (331). Although these observations
do not demonstrate the presence of a regulatory interaction, these experimental systems may be used in the
future to detect the potential presence of Sertoli cellderived paracrine factor(s). Several Sertoli cell secretory
products have been identified that may mediate regulatory interactions between Sertoli cells and germinal cells.
Insulin growth factor-I (IGF-I) has been shown to be
produced by Sertoli cells (83-86) and may act on meiotic
spermatogenic cells at IGF-I receptors (85, 332). IGF-I
has been shown to act on most cell types to maintain a
number of cellular functions and regulate DNA synthesis. Since IGF-I is a ubiquitous paracrine factor, actions
on germinal cells will likely be similar to those on somatic
February, 1991
CELL-CELL INTERACTIONS IN THE TESTIS
cells. Further investigation of IGF-I and IGF-I receptor
gene expression and production by cells of the seminiferous tubule is required. Examination of direct actions
of IGF-I on germinal cells is also needed to further
elucidate IGF-I mediated regulatory interactions between Sertoli cells and spermatogenic cells. Two other
Sertoli cell-derived growth factors that have not been
fully characterized, but are speculated to act on germ
cells, are the seminiferous growth factor (SGF) (333335) and Sertoli cell-secreted growth factor (SCSGF)
(336). The mitogenic properties of SGF and SCSGF,
however, have been demonstrated on somatic cells, but
not spermatogenic cells. Further investigation is required
to determine whether SGF or SCSGF may mediate regulatory interactions between these cells and promote
growth of developing germinal cells. Transforming
growth factors-a (TGFa) and 0 (TGF/3) have also recently been shown to be produced by Sertoli cells (81,
82) and potentially could influence germinal cells. Initial
studies imply that developing germinal cells do not contain the epidermal growth factor (EGF) receptor (81,
337). The actions of TGF« on spermatogenic cells, therefore, appear unlikely but remain to be thoroughly investigated. TGF0 is similar to IGF-I in that it is a ubiquitous
paracrine factor that acts on many cell types. TGF/? may
mediate a regulatory interaction between Sertoli cells
and germinal cells; however, the actions of TGF/3 on
spermatogenic cells remain to be elucidated. Other regulatory agents postulated to be produced by Sertoli cells
and act on germinal cells, such as interleukin-1 (IL-1)
that may stimulate germ cell growth (88, 190, 338) and
insulin growth factor-II (IGF-II) that may influence germ
cell metabolism (339), also require further examination
of both the sites of production and action of these potential paracrine factors.
Initial experiments to investigate the effects of germinal cells on Sertoli cells also utilized coculture of the
cells. The presence of germinal cells in culture with
Sertoli cells has been shown to influence Sertoli cell
protein glycosylation (340), increase basal and FSHstimulated ABP production by Sertoli cells (341-343),
inhibit estradiol production by Sertoli cells (343), and
influence the vectorial secretion of ABP by Sertoli cells
(344). Pachytene spermatocytes generally were found to
have more dramatic effects than late stage spermatids,
and the effects of germ cells on Sertoli cells may be age
dependent (343, 345). These observations have been extended through analysis of the effects of conditioned
medium obtained from spermatogenic cell cultures on
Sertoli cells. Germ cell-conditioned medium was found
to stimulate the phosphorylation of specific proteins in
Sertoli cells (346); stimulate 7-glutamyl transpeptidase
activity in Sertoli cells (347); increase ABP production
and decrease estradiol synthesis by Sertoli cells (348,
53
349); decrease RNA synthesis in Sertoli cells (350); increase transferrin production (351, 352) and transferrin
gene expression (353); and influence vectorial secretion
of proteins by Sertoli cells (352). Conditioned medium
from cultures of pachytene spermatocytes and early stage
round spermatids generally had the most dramatic effects. Initial characterization of the active component(s)
in the conditioned medium indicate the activity is heat
and trypsin sensitive (348,349). Partial purification demonstrated that the activity was present in a fraction
containing three polypeptides between 10 and 30 kilodaltons (353). Further purification and characterization
of the factors in germ cell conditioned medium are required to determine the number of potential factors
responsible for the biological activities and potential
identification of the paracrine factor. Due to the relatively poor viability of germ cells in culture, an important
consideration that will require investigation is whether
the paracrine factor(s) is actively secreted by germ cells
or simply present in germinal cell cytosol and derived
from cell lysis. In addition to the above analysis of
germinal cell-derived paracrine factors, nerve growth
factor (NGF) has also been postulated to be a paracrine
factor in the seminiferous tubule (354). /3-NGF gene
expression and NGF immunoreactivity have been identified in spermatocytes and early spermatids (355, 356).
NGF receptor gene expression has recently been identified in Sertoli cells under androgen regulation (354). The
observations that germ cells produce NGF and Sertoli
cells contain the NGF receptor have led these investigators to postulate that NGF may mediate regulatory
interactions between germinal cells and Sertoli cells.
Demonstration that these and other potential factors can
be secreted by germinal cells and subsequently act on
Sertoli cells remains to be elucidated.
The physiological significance of the regulatory interactions between Sertoli cells and germinal cells requires
further consideration. General factors required for the
maintenance of cellular function, such as IGF-I and
possibly TGF/3, are likely needed by all cell types. Therefore, developing germinal cells may also require these
same factors. Whether unique paracrine factors mediate
Sertoli-germinal cell interactions is unclear at present.
Spermatogenesis and meiosis are among the most evolutionarily conserved biological processes to assure propagation of the species. For this reason, the process of
germinal cell development and cellular associations has
been shown to be similar in a large number of different
animals (41). To maintain a high degree of stability and
conservation, the majority of regulatory elements required for spermatogenesis will likely be associated with
the genome of the germinal cell and require minimal
external regulatory interactions with other cell types.
Therefore, spermatogenesis may be a passive process,
54
SKINNER
and the primary Sertoli cell-germinal cell interactions
will be environmental and nutritional. Alternatively,
spermatogenesis may be an active process and require a
complex network of regulatory interactions to instruct
germinal cells to proceed from one stage of development
to the next. Further elucidation of Sertoli cell-germinal
cell interactions will elucidate the degree to which germinal cell development is an active or passive process.
B. Peritubular cell-Sertoli cell interactions
The stromal cells that surround the seminiferous tubule and are in contact with the basal surface of the
Sertoli cells are referred to as the peritubular myoid cells
(357-366). The widespread occurrence of peritubular
myoid cells among various species suggests that they are
an integral functional component of the mammalian
testis (357, 361-363, 365, 367). Differences in the thickness of the peritubular cell layers that surround the
tubule in different species, however, have been observed
(357, 362). The peritubular cells are thought to provide
structural integrity for the tubule and also appear to be
involved in contraction of the tubule (357, 362, 368, 369).
A peritubular cell sheath is present early in development
(370); however, myoid cells do not differentiate until the
early stages of puberty (359, 363, 371, 372) in response
in part to the actions of androgens (366,373). Alterations
in the peritubular cell layers have been shown to occur
in pathological conditions of the testis generally associated with an increased thickness of the tissue (374-380).
Peritubular cell-Sertoli cell interactions are postulated
to play an integral role in the maintenance of testis
function (reviews in Refs. 22 and 178).
Environmental. One of the primary environmental interactions between peritubular cells and Sertoli cells is
mediated by the complex extracellular matrix (i.e. basement membrane) between the two cell types. This extracellular matrix provides structural integrity for the tubule and assists in the maintenance of an efficient bloodtestis barrier (200). The junctional interactions between
peritubular cells and the extracellular matrix provide a
permeability barrier or prefilter while the tight junctional
interactions between Sertoli cells create a functional
blood-testis barrier. The extracellular matrix between
the peritubular cells and Sertoli cells appears to be
produced cooperatively by the two cell types (79, 381,
382). Sertoli cells in culture produce laminin and collagen
types I and IV (79) and unique proteoglycans (80). Peritubular cells in culture produce collagen type I (79),
unique proteoglycans (80), and fibronectin (79, 115).
Therefore, peritubular cells and Sertoli cells appear to
produce individual components of the basement membrane, and the presence of both cell types appears necessary to generate an organized deposited extracellular
Vol. 12, No. 1
matrix (79). The ability of peritubular cells and Sertoli
cells to cooperate in the production of this extracellular
matrix is postulated to be an essential environmental
interaction between the cells to form the basement membrane of the seminiferous tubule (79). Coculture of the
two cell types increased the attachment and viability of
Sertoli cells (383, 384) and altered the pattern and rate
of Sertoli cell migration (385, 386). Similar results have
been observed when Sertoli cells are cultured on a cell
line of peritubular cells (387). Since the primary environmental interactions between peritubular cells and Sertoli
cells are mediated by the extracellular matrix, a number
of laboratories have examined the effects of an extracellular matrix on Sertoli cells (388-392). The presence of
an extracellular matrix in culture was found to increase
cell attachment and viability, as well as promote a histotype that appears similar to that found in vivo with a
columnar shape cell, nucleus near the basal surface of
the cell, and tight junctions between Sertoli cells. Although the presence of an extracellular matrix can promote the structural differentiation of the Sertoli cell
(388, 389, 392), the extracellular matrix may not influence Sertoli cell functions on a molecular level (392);
that will require a regulatory type interaction. The presence of an extracellular matrix has also been shown to
promote peritubular myoid cells in culture to express a
morphology that is similar to that observed in the seminiferous tubule (393). Therefore, peritubular cells and
Sertoli cells cooperate in the production of the basement
membrane of the seminiferous tubule that, in turn, promotes structural differentiation of the peritubular cells
and Sertoli cells.
The observations that the presence of an extracellular
matrix promoted a columnar shaped cell in vitro with
tight junctions between Sertoli cells led several laboratories to develop dual-chamber culture systems to investigate polarized secretion by Sertoli cells (394-397). A
monolayer of Sertoli cells is placed on a permeable membrane to create an apical and basal chamber. The presence of an extracellular matrix was found to facilitate
the polarization of the cell and create a permeable barrier
(394). Sertoli cells secrete ABP, transferrin, plasminogen
activator, and inhibin in a polarized manner dependent
on the functional marker examined. Peritubular cells
were found to increase the efficiency of the permeability
barrier and altered the polarized secretion of Sertoli cell
products (398-402). Therefore, an additional environmental interaction between peritubular cells and Sertoli
cells is to promote and maintain the polarity of the
Sertoli cell and vectorial secretion of cellular products.
Proteases and antiproteases are additional cellular
products that can influence the environmental interactions between peritubular cells and Sertoli cells. Sertoli
cells produce plasminogen activator (72), which could be
•
February, 1991
CELL-CELL INTERACTIONS IN THE TESTIS
involved in the degradation and turnover of the basal
lamina of the tubule and influence the junctional interaction between Sertoli cells. Peritubular cells have been
shown to produce a protease inhibitor that inhibits plasminogen activator activity (120). The production of the
antiprotease by peritubular cells, therefore, might regulate the level of protease activity present to control
degradation of the extracellular matrix between Sertoli
cells and peritubular cells, as well as maintain the bloodtestis barrier (120). This hypothesis is supported by an
investigation of the effects of proteases and antiproteases
on the permeability barrier of Sertoli cells in a dualchamber culture system (400).
Nutritional. Both Sertoli cells and peritubular cells are
in contact with interstitial fluid such that essential components from the circulatory system can readily be obtained by both cell types. Junctional interactions between Sertoli cells and gap junctions between peritubular
cells (200) can facilitate nutritional interaction between
the individual cell types. Sertoli cells in vitro have been
shown to metabolically cooperate with peritubular cells
(403) and fibroblasts (404) through junctional contacts
and transport metabolites such as nucleotide precursors.
The presence of the basal lamina of the seminiferous
tubule, which separates peritubular cells and Sertoli cells,
however, prevents junctional contacts to form between
the cells (200). Therefore, the metabolic cooperation
observed in vitro between the cells is likely not present
in vivo. Nutritional interactions between peritubular
cells and Sertoli cells may not be important due to the
availability of serum components to both cell types and
lack of junctional interactions between the cells in vivo.
Regulatory. Regulatory interactions between peritubular
cells and Sertoli cells were first postulated when it was
observed that androgens alone could not promote peritubular cell differentiation, but gonadotropin action on
Sertoli cells was also required to indirectly effect peritubular cell differentiation (366). Coculture of Sertoli
cells and peritubular cells indicates that the presence of
peritubular cells increases the production of ABP by
Sertoli cells (383, 405); stimulates transferrin production
by human Sertoli cells (406); alters the enzyme histochemistry of Sertoli cells (407); and influences the vectorial secretion of proteins by Sertoli cells (398, 401,
408). These observations imply that peritubular cells
may influence Sertoli cell functions through a regulatory
type interaction. Peritubular cells were subsequently
shown to produce a nonmitogenic paracrine factor that
modulates Sertoli cell function and has been termed
PModS (117, 409). Serum-free peritubular cell-conditioned medium was found to stimulate the production of
a number of proteins by Sertoli cells including ABP and
transferrin (117, 409, 410). PModS has been purified and
55
characterized and found to have a more dramatic effect
on Sertoli cell functions in vitro than any individual
regulatory agent previously identified, including FSH
(118). An illustration of the effect of PModS on Sertoli
cell function in comparison with other hormones is
shown in Fig. 5. PModS is shown to stimulate transferrin
production by Sertoli cells in culture to the same extent
as a mixture of FSH, insulin, and retinol. A combination
of PModS and these hormones results in an additive
response with an 8- to 10-fold stimulation of Sertoli cell
function. The actions of PModS on transferrin and ABP
production correlate with an increase in steady state
levels of messenger RNA, and the dramatic effects of
PModS appear to be due to the signal transduction
system utilized (119). Although PModS stimulates most
functions associated with the differentiation of the cell,
cellular functions apparently independent of Sertoli cell
differentiation, such as aromatase activity, may be suppressed by PModS (411). The hypothesis has developed
that PModS may have an important role in the induction
and maintenance of Sertoli cell differentiation (22, 118,
119,188). The in vivo actions of PModS, however, remain
to be investigated.
Additional paracrine factors that have been identified
to potentially mediate regulatory interactions between
peritubular cells and Sertoli cells are growth factors. The
EGF-like substance, TGFa has been shown to be synthesized and secreted by Sertoli cells and peritubular
cells (81). The EGF-like growth factor previously shown
to be produced by Sertoli cells (87) is thought to be TGFa
(81). Functional EGF/TGFa receptors are expressed on
peritubular cells but not Sertoli cells or germinal cells
(81). Immunolocalization of the EGF receptor, however,
indicated that the EGF receptor may be on Sertoli cells
(337). TGFa/EGF stimulates peritubular cell growth but
not Sertoli cell growth (81). EGF has been shown to
influence Sertoli cell functions (412, 413); however, several Sertoli cell functions were not found to be influenced
by TGFa/EGF in highly purified preparations of Sertoli
cells (81). Further examination of the cellular localization of EGF receptor expression and the actions of EGF/
TGFa in the seminiferous tubule is required to elucidate
the role TGFa may have in regulatory interactions between peritubular cells and Sertoli cells.
TGF/3 is a growth inhibitor that has also been shown
to be produced by Sertoli cells and peritubular cells (82).
TGF/3 can inhibit TGFa/EGF-stimulated peritubular
cell growth and promote peritubular cell migration and
colony formation (82). TGF/3 appears to promote the
differentiation of peritubular cells and can increase the
production of specific proteins (82) such as the plasminogen activator inhibitor antiprotease (414). TGF/3 may
also promote peritubular cell chemotaxis to assist in the
morphogenesis of the seminiferous tubule (82). TGF/3
56
SKINNER
does not appear to have general effects on major Sertoli
cell functions (82); however, TGF/3 may increase lactate
production by Sertoli cells (415). Further examination of
the production and action of TGF/3 in the tubule is
required to determine the importance TGF/3 may have
in mediating peritubular cell-Sertoli cell interactions.
Another growth factor produced by peritubular cells
and Sertoli cells is IGF-I, which is a somewhat ubiquitously expressed growth factor that maintains cellular
metabolism and acts as a progression factor in the growth
of most cell types. IGF-I has been shown to directly
stimulate a number of Sertoli cell functions and facilitate
the growth of peritubular cells and prepubertal Sertoli
cells. Examination of the cellular localization of IGF-I
and IGF-I receptor gene expression in the seminiferous
tubule (83-86, 416-419) and the actions of IGF-I is
required to elucidate whether locally produced IGF-I may
mediate peritubular cell-Sertoli cell interactions. The
high concentration of IGF-I in the interstitial fluid derived from the circulatory system is readily available to
both cell types; therefore, the physiological need for
actions of a locally produced IGF to mediate peritubular
cell-Sertoli cell interactions needs to be questioned.
C. Sertoli cell-Leydig cell interactions
The specialized cells within the interstitial tissue of
the testis referred to as Leydig cells (420) were distinguished morphologically by a number of early investigators (31-33). The functional importance of this cell was
realized with the demonstration that Leydig cells are the
site of androgen production (421-426) and that LH
through the actions of cAMP directly stimulates androgen production (427-431). The local action of androgen
on testis function was initially demonstrated when testosterone alone in the absence of gonadotropins was
shown to support spermatogenesis (432) at significantly
reduced androgen levels as observed in vivo (433, 434).
Androgens, therefore, were the first paracrine agents
involved in cell-cell interactions in the testis to be investigated. These observations initiated a relatively intense
analysis of Sertoli cell-Leydig cell interactions.
Environmental. The location of Leydig cells in the interstitium and the presence of peritubular myoid cells and
the basement membrane of the seminiferous tubule do
not allow for physical contact between Sertoli cells and
Leydig cells. The inability of these cells to physically
interact indicates that direct environmental interactions
between Sertoli cells and Leydig cells are not possible in
vivo.
Nutritional. Both Sertoli cells and Leydig cells have
ready access to essential nutritional components in the
interstitial fluid derived from the circulatory system. For
Vol. 12, No. 1
this reason, and because the cells are unable to form
junctional contacts, nutritional interactions between
Sertoli cells and Leydig cells appear minimal. Leydig
cells, however, have been shown to have junctional interactions between themselves (435-439) that can mediate nutritional interactions. Cooperativity between
Leydig cells mediated by steroids (440-442) and nonsteroidal substances (443, 444) has been observed.
Regulatory. The identification of androgen production by
Leydig cells (421-431) and the ability of androgens to
maintain the process of spermatogenesis (432-434) led a
number of laboratories to investigate the actions of androgens on Sertoli cells. Sertoli cells have been shown to
contain and express the androgen receptor (445-451),
which is influenced by hormones, sexual maturation, and
the cycle of the seminiferous epithelium (452-457). The
actions of androgens on Sertoli cell function have been
investigated, and the effects observed in vitro are generally negligible or less than the actions of FSH (303, 458462) as shown in Fig. 5. Although the androgen receptor
is present in Sertoli cells, a complete understanding of
the role of androgen actions on Sertoli cells requires
further investigation. The ability of peritubular cells to
enhance the actions of androgen on Sertoli cells, however, suggests that androgens may indirectly regulate
Sertoli cell function and points out the importance of
using a purified preparation of Sertoli cells to investigate
the actions of androgens (463). Current data imply that
an important regulatory interaction between Leydig cells
and Sertoli cells is mediated through the local production
and action of androgens, but the physiological significance of this regulatory interaction remains to be fully
elucidated.
In addition to androgens, Leydig cells can potentially
influence Sertoli cells through nonsteroidal factors. A
number of peptides and proteins have been shown to be
produced or localized in Leydig cells that can potentially
have a regulatory action on Sertoli cells and the seminiferous tubule including renin (464-467), prodymorphin
(468), and oxytocin (469-471). The functional and physiological roles of these peptides, however, remain to be
investigated. Another peptide produced by Leydig cells
that may regulate Sertoli cell and seminiferous tubule
function is POMC and related peptides (108-112, 472474). Several peptides that are derived from the POMC
protein and appear to be produced by Leydig cells include
0-endorphin, aMSH, and ACTH (108, 475). These peptides have been postulated to be involved in the regulation of Sertoli cell function (476-478). The actions of /?endorphin, aMSH, and ACTH on Sertoli cell function
have been examined (479-485). The stimulating effects
of aMSH and ACTH on Sertoli cell function are small
and appear to involve in vitro alterations in cAMP levels.
February, 1991
CELL-CELL INTERACTIONS IN THE TESTIS
The j8-endorphin receptor has been shown to be present
on Sertoli cells (479). Although /?-endorphin alone was
found to have little effect, /3-endorphin can partially
decrease the ability of FSH to stimulate Sertoli cell
functions. The concentrations of these POMC peptides
required to obtain effects on Sertoli cells in vitro were
relatively high, and these peptides have not been shown
to have dramatic effects on Sertoli cell function in comparison with factors such as FSH. Perfusion of the testis
with these peptides revealed that ACTH, but not aMSH
or /3-endorphin, can influence androgen production by
Leydig cells (486, 487). Further work is required to
determine the physiological significance of POMC-derived peptides and their importance in mediating regulatory interactions between Leydig cells and Sertoli cells.
The ability of Sertoli cells and the seminiferous tubules
to affect Leydig cell function was initially hypothesized
from observations that Leydig cell morphology was altered by tubules with abnormal function and spermatogenesis (488, 489). Damage of seminiferous tubule function with cytotoxic agents, vitamin A deficiency, or fetal
irradiation was found to cause abnormal cytological features and function in adjacent Leydig cells (490). Analysis of testis morphology under pathological conditions
(49i-493) and in aged man (494) supports the interrelationship of the seminiferous tubules and Leydig cells.
Cryptorchidism has been extensively utilized to inhibit
seminiferous tubule and Sertoli cell function to examine
subsequent effects on Leydig cell function and morphology (495-502). In addition to studies with damaged or
abnormal testis, examination of normal testis has revealed that Leydig cell morphology changes with the
seminiferous cycle being most dramatic at stages VII and
VIII (503-505). These morphological studies of both
abnormal and normal testis implied that a regulatory
interaction may exist between Sertoli cells and Leydig
cells. To extend these observations, several laboratories
cocultured Leydig cells with Sertoli cells or seminiferous
tubules. Sertoli cells were found to generally increase
basal and hormone-stimulated Leydig cell functions, and
FSH was found to indirectly, through the Sertoli cell,
stimulate Leydig cell steroidogenesis (506-512). Seminiferous tubules in coculture, particularly at stages VI
and VIII, were also found to influence Leydig cell function (513, 514).
Further examination of this potential regulatory interaction between Sertoli cells or seminiferous tubules utilized conditioned culture medium. A number of laboratories have identified a stimulatory activity in Sertoli
cell-conditioned medium that increases both basal and
hormone-stimulated Leydig cell function (515-527).
Both FSH-dependent and -independent activities have
been identified. Inhibitory activities in the conditioned
medium that can decrease basal and hormone-stimulated
57
Leydig cell steroidogenesis have also been identified
(528-535). An interesting study with the use of spent
media from seminiferous tubules isolated from normal
and cryptorchid testis revealed that under normal conditions predominantly inhibitory activity was present
whereas cryptorchidism induced the appearance of stimulatory activity (536). Although the contributions of
germinal cells and peritubular myoid cells to the activities in conditioned medium from seminiferous tubules
remain to be elucidated, observations imply that Sertoli
cells may produce multiple factors that can influence
Leydig cell function and size. Purification and characterization of these Sertoli cell products are required to
determine the novelty of the substances investigated and
to address the physiological significance of this proposed
regulatory interaction between Sertoli cells and Leydig
cells. Additional indirect support of the presence of local
factor(s) in the testis that can regulate Leydig cell function is provided with the observations that testicular
interstitial fluid has the ability to stimulate Leydig cell
steroidogenesis (537-546). The stimulatory activity present in interstitial fluid is speculated to be derived from
Sertoli cells; however, further analysis of the sites of
action, sites of production, and biochemical properties of
the active components is required.
Several Sertoli cell-secretory products have been identified that can potentially mediate regulatory interactions between Sertoli cells and Leydig cells. One of the
first paracrine factors considered was estrogen. Sertoli
cells can produce estrogen from androgens (92, 547), and
estrogen generally has inhibitory effects on Leydig cell
androgen production (548, 549). The proposal has been
made that Sertoli cell-derived estrogen may mediate
inhibitory actions on Leydig cell testosterone production;
however, Leydig cells can also produce relatively high
levels of estrogen (550), which could act as an autocrine
factor for the cell. The physiological significance of estrogen-mediated regulatory interactions between Sertoli
cells and Leydig cells, therefore, remains to be elucidated.
Another factor postulated to be produced by Sertoli cells
that can act on Leydig cells is a LHRH-like substance
(551-557). Leydig cells from some species have been
shown to contain receptors for LHRH (551, 558-561),
and LHRH generally has long term inhibitory effects on
Leydig cell steroidogenesis (562, 563). The production of
an LHRH-like substance by Sertoli cells, however, has
been questioned (564) and appears to be somewhat species specific in both the production and action of an
LHRH-like substance. Although altered molecular forms
of an LHRH molecule may be present in the testis (565567), further analysis of species specificity, sites of production, sites of action, and biochemical characterization
of such substances will be required.
Sertoli cells also produce a number of growth factors
58
SKINNER
that potentially mediate Sertoli cell-Leydig cell interactions. IGF-I is produced by Sertoli cells (83-86, 568-570)
and can act on Leydig cells to regulate steroidogenesis
(571-576). The ability of Sertoli cells to stimulate Leydig
cell steroidogenesis in coculture of the two cell types can
be partially inhibited with immunoneutrilization with an
IGF-I antibody (577). Leydig cells, however, can produce
IGF-I (114) that can act as an autocrine factor for the
cell. In addition, the concentration of liver-derived IGFI in the circulatory system and interstitial fluid is approximately 2 orders of magnitude higher than the
concentrations required to influence Leydig cell steroidogenesis. Therefore, the physiological relevance of an
IGF-I mediated regulatory interaction between Sertoli
cells and Leydig cells is questioned. Two other growth
factors produced by Sertoli cells are TGFa and TGF/?
(81, 82). Leydig cells contain the EGF/TGFa receptor
and can respond to EGF or TGF« to influence steroidogenesis and cell growth (578-581). The potential production of TGFa/EGF by Leydig cells (582) or interstitial
cells would question the importance of a paracrine interaction between Sertoli cells and Leydig cells. Leydig cell
steroidogenesis can also be influenced by the actions of
the growth inhibitor TGF/? (583-586). The TGF0 produced by Sertoli cells (82, 587) could act as a paracrine
factor to regulate Leydig cell function and growth, but
further investigation of additional sites of TGF0 production and action is required to elucidate the physiological
relevance of this potential cell-cell interaction.
Inhibin (588) is a peptide hormone produced by Sertoli
cells (reviews in Refs. 93, 589, and 590) under the control
of FSH or agents that alter cAMP levels (591-596).
Although a major function for inhibin is to act on the
pituitary to regulate FSH production, potential local
actions of inhibin have been postulated. Inhibin and its
related protein activin both can influence Leydig cell
steroidogenesis (597,598). Therefore, inhibin may potentially mediate a regulatory interaction between Sertoli
cells and Leydig cells. Leydig cells have been postulated
to be involved in the regulation of Sertoli cell inhibin
production (599, 600); however, Leydig cells have also
been shown to produce both inhibin and activin (113,
601-603). The ability of both Sertoli cells and Leydig
cells to produce inhibin and related peptides questions
the relevance of a paracrine interaction between the cells
mediated by inhibin. The observation that other cell
types, such as germinal cells (604), may provide additional sites of action for inhibin or activin suggests that
an understanding of the role inhibin/activin has in testicular cell-cell interactions will require further investigation of the sites of action and sites of production of
inhibin/activin. Potential alternate or new biological activities of forms of inhibin such as the pro-a-c region of
the inhibin subunits also needs to be examined. The role
Vol. 12, No. 1
TABLE 5. Sertoli cell-Leydig cell regulatory interactions
Potential
paracrine factor
Site
production
Site
action
Actions/
proposed function
Androgen
Leydig
Sertoli
Regulate/maintain
function and
differentiation
POMC peptides
/?-endorphin
Leydig
Sertoli
MSH, ACTH
Stimulatory factor
(?) (FSH dependent or independent)
Inhibitory factor
(?)
LHRH-like factor
Sertoli
Leydig
Sertoli
Leydig
Sertoli
Leydig
Estrogen
Sertoli
Leydig
IGF-I
Sertoli
Leydig
TGFa
Sertoli
Leydig
TGFjf?
Sertoli
Leydig
IL-1
Sertoli
Leydig
Inhibin
Sertoli
Leydig
Decrease FSH actions
Increase FSH actions/cAMP
Increase steroidogenesis
Decrease steroidogenesis
Decrease steroidogenesis
Decrease steroidogenesis
Increase steroidogenesis
Decrease steroidogenesis/increase
growth
Increase steroidogenesis
Decrease steroidogenesis
Increase steroidogenesis
inhibin and its related peptides may have in the local
regulation of testis function remains to be elucidated.
A number of potential paracrine factors may mediate
regulatory interactions between Sertoli cells and Leydig
cells (Table 5). Additional regulatory agents that can
influence Leydig cell function, such as IL-1 (605, 606)
and vasopressin-like peptides (607), may also be involved
in this interaction but require further investigation. The
biological activities present in conditioned medium will
require biochemical characterization in order that the
potential role these agents may have in cell-cell interactions may be understood. Many of the stimulatory and
inhibitory effects observed with materials such as Sertoli
cell-conditioned medium may potentially be attributed
to the known regulatory agents investigated, such as
IGF-I, IL-1, TGFa, or TGF0. Although a list of potential
paracrine factors is developing, further analysis is necessary to elucidate their involvement in cell-cell interactions and physiological relevance.
Although the production of androgen by Leydig cells
and subsequent action on the seminiferous tubule is an
essential regulatory interaction to maintain testis function, the physiological requirement for Sertoli cell-Leydig
cell regulatory interactions requires further considera-
i
A
1
A
February, 1991
CELL-CELL INTERACTIONS IN THE TESTIS
tion. The concentration of androgen present in the adult
testis is significantly higher than the concentrations
needed to maintain germinal cell development (608-611).
Local transient alterations in androgen production by
80-90% may not have major effects on Sertoli cell or
germinal cell development. A stimulation in androgen
production would not appear to be important for adult
testis function. Although an active regulation of Leydig
cell androgen production may be needed during embryonic, postnatal, and pubertal development, in the adult
testis regulatory interactions between Sertoli cells and
Leydig cells to influence Leydig cell steroidogenesis may
not be physiologically important. Additional functions of
the Leydig cells, however, may need to be activity regulated.
D. Leydig cell-peritubular cell interactions
The Leydig cell and peritubular myoid cell are both
thought to be derived from the pluripotential urogenital
mesenchyme. Although peritubular myoid cell differentiation occurs postnatally, Leydig cells appear to develop
from precursor mesenchymal cells located in the peritubular region during fetal development (612, 613), and
this development is thought to be similar to the pattern
of Leydig cell development during postnatal life (438,
614). The origins of the Leydig cells and peritubular
myoid cells, therefore, are closely associated. These cell
types are not terminally differentiated, and both peritubular cells and Leydig cells proliferate in the adult and
have a defined turnover time (615). The development
and proliferation of these cell types require a continuous
association between Leydig cells and peritubular myoid
cells.
Environmental. In the adult tissue Leydig cells in the
interstitium do not generally form a physical contact
with differentiated peritubular myoid cells surrounding
the tubule and in contact with the basal surface of the
Sertoli cell. Outer layers of less differentiated peritubular
myoid cells and undifferentiated fibroblasts or stromal
cells and lymphatic endothelium generally separate Leydig cells from myoid cells. The inability of these cells to
physically interact indicates that direct environmental
interactions between Leydig cells and peritubular myoid
cells are generally not present in the adult testis. During
development, however, less mature or differentiated Leydig cells and peritubular cells may potentially form environmental interactions.
Nutritional. Both Leydig cells and peritubular myoid
cells have ready access to essential nutritional components in the interstitial fluid derived from the circulatory
system. The lack of apparent junctional interactions
between these cell types and ready access to nutritional
59
components implies that minimal nutritonal interactions
between Leydig cells and peritubular myoid cells are
needed. Although Leydig cells appear to interact among
themselves (435-444), no apparent nutritional interactions between Leydig cells and peritubular myoid cells
have been observed.
Regulatory. The primary regulatory interaction identified
between Leydig cells and peritubular myoid cells is mediated by androgens. Peritubular myoid cell development
is postulated to be dependent on androgens (366, 373).
Inhibition of the androgen production by Leydig cells or
the presence of antiandrogens will interfere with peritubular myoid cell development. The peritubular cells accumulate androgen (46) and contain the androgen receptor (456, 616, 617). The level of androgen receptor present in peritubular cells is approximately the same as
present in Sertoli cells (617). Peritubular cells in organ
culture (373) and isolated peritubular cells in culture
respond to androgens (117, 161, 411, 463). The production of the testicular paracrine factor PModS by peritubular cells appears to be under androgen control (117,
463). Therefore, a cascade of cellular interactions is
speculated to occur in response to LH and androgen. LH
acts on Leydig cells to stimulate the production of androgen that subsequently acts on peritubular myoid cells
to stimulate PModS production that modulates Sertoli
cell functions and nutritional interactions essential for
germinal cell development (117-119). This androgenmediated regulatory interaction between Leydig cells and
peritubular cells involving PModS is postulated to be
important for the maintenance of testis function and the
process of spermatogenesis (22, 118, 119, 188). Further
analysis of the in vivo actions of PModS is required to
determine the physiological importance of this cell-cell
interaction.
Additional Leydig cell products that influence peritubular myoid cells have not been identified. Further analysis of biochemical markers for peritubular cell function,
such as PModS, will be needed to elucidate potential
nonsteroid-mediated regulatory interactions between
Leydig cells and peritubular cells. Peritubular cell products that may act as paracrine factors and influence
Leydig cell function include IGF-I (114), the EGF-like
substance TGF« (81), and TGF/3 (81). IGF-I and TGF0
may potentially stimulate Leydig cell steroidogenesis
(571-576, 583-586) whereas TGFa may regulate Leydig
cell growth and steroidogenesis (578-581). Although
these growth factors are produced by peritubular cells
and can act on Leydig cells, the role of these growth
factors in mediating cell-cell interactions requires further
investigation. The high concentration of serum-derived
IGF-I in the interstitial fluid makes questionable the role
of IGF-I as a mediator of regulatory interactions between
60
SKINNER
the cells. Further analysis of TGFa- and TGF0 production and action in the interstitial tissue is also needed
before speculations regarding their involvement in cellular interactions between Leydig cells and peritubular
myoid cells can be postulated.
The androgen-mediated regulatory interactions between Leydig cells and peritubular myoid cells provide a
potentially important indirect mode of androgen action
in the testis. Therefore, the peritubular cells may play a
critical role in the endocrine regulation of the process of
spermatogenesis. The dramatic effects of PModS on
Sertoli cell function and inability of purified Sertoli cells
to respond to androgens in vitro support these speculations of the importance of this indirect mode of androgen
action. Peritubular cell-Sertoli cell interactions provide
an example of mesenchymal-epithelial cell interactions
present in a variety of tissues. Steroid actions on tissues
have been postulated to, in part, be mediated through
mesenchymal-epithelial cell interactions (review in Ref.
11). The prostate stromal/mesenchymal cells, in response to androgens, appear to produce an inducer substance that regulates the functions and differentiation of
the adjacent prostatic-epithelial cells (618-620). This
proposed cell-cell interaction is similar to that proposed
between Leydig cell cells, peritubular myoid cells, and
Sertoli cells. The possibility that PModS may be a general mediator of androgen actions in other organs in
addition to the testis has previously been postulated (22,
118), and preliminary evidence was provided with prostate cell culture-conditioned medium (621, 622). Further
characterization of PModS and its potential expression
and action in androgen-responsive tissues will be required to determine its tissue specificity.
E. Additional cell-cell interactions
Although the Leydig cells, peritubular myoid cells,
Sertoli cells, and germinal cells are major functional cell
types in the testis, several additional existing cell populations include the vasculature and lymphatic endothelium, lymphocytes, macrophages, and the stromal fibroblast cell population. Several studies have been initiated
to investigate the physiology of these cell populations
and their potential involvement in cell-cell interactions.
The stromal fibroblast population of cells in the interstitium and surrounding the outer layers of the seminiferous tubules is thought to contribute to the structural
integrity of the tissue as well as contain a stromal/
mesenchymal cell population from which Leydig cells
and peritubular myoid cells have been speculated to be
derived. Because Leydig cells and peritubular myoid cells
proliferate and have a limited turn over time, a less
differentiated population of precursor cells or a stem cell
population of stromal/mesenchymal cells appears nec-
Vol. 12, No. 1
essary to repopulate the cell types. Whether the Leydig
cells and peritubular myoid cells are derived from the
same precursor population of cells or separate precursor
cell types is unclear. Studies to investigate the potential
involvement of these cells in cellular interactions have
focused on Leydig cells. Treatment of rats with the
cytotoxic agent ethane dimethanesulfonate (EDS) has
been found to destroy the mature Leydig cell population
(623-625). Although EDS does influence Sertoli cell and
peritubular myoid cell functions (626, 627), EDS has
been utilized to examine Leydig cell regeneration and
interactions with other cell types (628-632). Repopulation of Leydig cells after removal of EDS suggests that
the Leydig cells are derived from the stromal fibroblast
population of cells often associated with the outer layer
of cells of the seminiferous tubule (628, 630-632). The
regeneration of the Leydig cells from this stromal fibroblast population is speculated to be influenced by the
seminiferous tubules and Sertoli cells for growth and
possibly differentiation (629, 631, 632). Analysis of cell
proliferation and pulse-chase radiolabeling experiments
of the stromal/mesenchymal cell population, in comparison to other testicular cell types, support the hypothesis
that Leydig cells may be derived from this cell population
(633). These stromal/mesenchymal precursor cells can
be isolated and cultured and appear to be responsive to
the combined actions of LH and androgen (634). Further
analysis of cellular interaction with this Leydig cell precursor population of stromal fibroblast cells requires
characterization of the cell population and identification
of functional parameters of the cells.
Another cell population in the testis is derived from
the immune system. Macrophages have been shown to
reside in the interstitial compartment of the testis (635637). These testicular macrophages have been isolated
and characterized (638). Testicular macrophages often
physically associate with Leydig cells, and speculations
of potential cellular interactions between the cells have
been made (639). Interestingly, the conditioned medium
from testicular macrophage cultures has been shown to
stimulate Leydig cell steroidogenesis (640). Although
testicular macrophages will likely have traditional bactericidal and phagocytic activities in the testis (641-647),
potential environmental and regulatory interactions between testicular macrophages and other testis cell types,
particularly Leydig cells, may also exist. Lymphocytes
are also present in the testis and participate in the
normal immunology of the animal. The testis, however,
has been shown to be an immunologically protected
tissue (648-651). Potential cellular interactions between
testis cell types and these lymphocytes remain to be
thoroughly investigated. Several testis cell products may
interact with the lymphocyte population present. Sertoli
cells appear to produce protein(s) that can inhibit lym-
February, 1991
CELL-CELL INTERACTIONS IN THE TESTIS
phocyte proliferation (98, 652). The apparent Sertoli cell
product IL-1 (88) may also potentially act as a paracrine
factor to influence lymphocytes. Products of testis cell
types may be needed to regulate local lymphocyte functions important for immunological protection of the tissue (653-655). In contrast, lymphocyte products, such as
interferon and tumor necrosis factor, may be needed to
influence testis cell functions (656-658). Further investigation of the reproductive immunology of the testis
(652) is required to determine specific regulatory interactions between immune system cells, such as macrophages and lymphocytes, with other cell types in the
testis.
Vascular and lymphatic endothelial cells are also relatively abundant cell populations in the testis. The arteries, veins, and capillaries that vascularize the testis at
puberty are generally associated with the tubules (659662). The permeability of this vasculature is relatively
high such that substances introduced into the circulation
equilibrate with testicular lymph (207, 260, 663). Potential interactions between this vasculature and other testicular cells, particularly the seminiferous tubule, may be
mediated by angiogenic factors. Fibroblast growth factor
(FGF) is one of the most potent and well characterized
angiogenic factors that promotes the vascularization of
tissues (664). FGF has been shown to be present in testis
extracts (665, 666); however, the site of synthesis of
testicular FGF remains to be elucidated. The ability of
testis cells to produce FGF as an angiogenic factor to
promote and maintain vascularization of the testis constitutes a potentially important regulatory cell-cell interaction. Other paracrine factors that may mediate regulatory interactions between the vasculature and other
testis cell types, such as the renin-angiotensin or atrial
natriuretic peptides, remain to be investigated. In addition to the vasculature, lymphatic endothelium often
associates with the outer peritubular wall and envelops
the Leydig cells (667-669). Although the association of
lymphatic endothelium with tubules is variable among
species, this cell population is thought to be important
in the formation of the interstitium compartment and
support of testicular lymph.
61
III. Summary
A. Testicular cell-cell interactions
A general summary of the major categories of cell-cell
interactions among the primary testicular cell types considered are illustrated in Table 6. The major environmental interactions occur between Sertoli cells and spermatogenic cells and between peritubular cells and Sertoli
cells. The lack of physical contact between Leydig cells
and Sertoli cells or peritubular myoid cells indicates that
environmental interactions between these cells will not
likely be an essential cell-cell interaction. The primary
nutritional interaction in the testis is between Sertoli
cells and germinal cells. Ready access to serum-derived
nutritional components in interstitial fluid by the other
cell types indicates that major nutritional interactions
between Leydig, peritubular, and Sertoli cells will not be
required. Regulatory interactions occur among all the
cell types considered. Although further investigation of
regulatory interactions between Sertoli cells and germinal cells is needed, initial studies suggest the presence
of such interactions. Observations imply that the cellular
anatomy of the testis and factors such as the blood-testis
barrier play a major role in the types of cell-cell interactions that have evolved and are needed to maintain
testis function. The cellular associations and physiology
of the testis, however, differ depending on the stage of
development. Therefore, the cell-cell interactions required and present in the prenatal testis, prepubertal
testis, pubertal testis, and adult testis will be altered
depending on the specific physiological requirements. As
specific cellular interactions are more thoroughly characterized in the more mature stages of development, their
role in the developing testis can be examined.
Several aspects of testis cell biology that are integrally
associated with local cellular interactions involve growth
and differentiation. All testicular cell types prepubertally
require cell proliferation, which terminates for Sertoli
cells at the early stages of puberty. All other testicular
cell types, except Sertoli cells, require varying degrees of
cell proliferation in the adult testis. Therefore, the local
production and action of growth factors are required to
regulate testis cell growth (review in Ref. 670). These
TABLE 6. Classification of testicular cell-cell interactions
Interaction
Sertoli-germinal
Peritubular-Sertoli
Sertoli-Leydig
Leydig-peritubular
Environmental
Nutritional
Regulatory
Yes
(e.g. cytoarchitecture)
Yes
(e.g. basement membrane)
No
Yes
(e.g. transport proteins)
No
Yes
(e.g. IGF-I)
Yes
(e.g. PModS)
Yes
(e.g. POMC peptides)
Yes
(e.g. androgen)
No
No
No
SKINNER
62
growth factors can act as autocrine and paracrine factors
to mediate regulatory interactions among various testis
cell types. The majority of proposed potential growth
factor-mediated cell-cell interactions are outlined in Fig.
6. All of these proposed interactions require further
investigation to elucidate their physiological relevance.
IGF-I can potentially mediate interactions between all
the cell types; however, due to the high concentration of
serum-derived IGF-I present in the interstitium, only
Sertoli cell-germinal cell IGF-I-mediated interaction
may be important. TGFa and TGF/3 have antagonist growth effects and may also mediate interactions
between all the cell types, but further analysis of the
sites of production and action of TGF« and TGF/3 is
required. IL-1 has been postulated to be produced by
Sertoli cells and potentially interact with Leydig cells
and germinal cells. Interactions of IL-1 with other testicular cell types such as macrophages and lymphocytes
may be of equal or greater physiological importance for
testis function. FGF has been shown to be present in the
testis (665, 666); however, the site of synthesis of testicular FGF remains to be determined. FGF has the ability
to influence Leydig cell (671-674) and Sertoli cell function (675); however, potential actions on lymphatic and
vascular endothelial cells may be of equal or greater
physiological relevance. Other potential testicular
growth factors that require further characterization such
as SGF (333, 334) and SCSGF (336) may also mediate
cell-cell interactions. Clearly, locally produced growth
factors in the testis will be important mediators of regulatory interactions between various cell types; however,
further investigation is needed to elucidate the specific
interactions and growth factors that will be physiologically relevant in the regulation of testis cell growth.
Classical growth factors such as FGF or EGF/TGFa
act to promote a cell into the growth cycle, and subsequently a progression factor such as IGF-I will facilitate
DNA synthesis followed by the proliferation of the cell.
Vol. 12, No. 1
The function and pharmacology of these growth factors
are directed toward putting the cell into the cell cycle to
allow cell proliferation. Differentiation of a cell is generally independent of cell growth and may require a
separate class of regulatory agents to promote and maintain the differentiated state of the cell. Optimal differentiation of the cell often requires the cell to be at a
specific stage of the cell growth cycle. Alteration of the
cell cycle by growth factors, therefore, may indirectly
affect cellular differentiation. As with most organs, the
testis requires a set of differentiation type regulatory
agents to promote development, control function, and
maintain cellular differentiation. Although identification
and analysis of differentiation type factors is generally
more difficult than analysis of growth factors, a summary
of the regulatory agents involved in cell-cell interactions
is shown in Fig. 7. The endocrine hormones LH and
FSH play an integral role in promoting and maintaining
Leydig cell and Sertoli cell function, respectively. Androgen production by Leydig cells promotes and maintains
the differentiation and function of peritubular myoid
cells and Sertoli cells. PModS derived from peritubular
cells appears to promote and control Sertoli cell function
and differentiation. TGF/3 is generally a growth inhibitor
that stops cell growth and puts the cell into a stage in
the cell cycle more responsive for optimal differentiation.
Therefore, TGF/3 can indirectly act as a differentiation
factor by inhibiting growth. TGF/3 has been shown to
stimulate Leydig cell and peritubular cell function, and
its potential role on germinal cells remains to be investigated. Inhibin/activin are also regulatory agents with
hormone-like differentiation properties that are likely
independent of growth similar to TGF/3. Inhibin has been
postulated to be involved in Sertoli cell-Leydig cell interactions; however, further analysis of the sites of production and action of inhibin/actin is needed to fully
elucidate involvement in cell-cell interactions. Further
investigation of these and additional differentiation fac-
Leydig
TGF0
Peritubular
Sertoli
Germinal
FIG. 6. Potential growth factor-mediated cell-cell interactions in the
testis.
Peritubular
Sertoli
Germinal
FlG. 7. Potential cell-cell interactions that regulate cellular differentiation.
February, 1991
63
CELL-CELL INTERACTIONS IN THE TESTIS
tors is needed to fully understand the specific regulatory
interactions involved in the control and maintenance of
cellular differentiation in the testis.
B. Endocrine regulation of testis function
Analysis of cell-cell interactions in the testis has revealed that the actions of the endocrine system are often
indirectly mediated through local cellular interactions.
Leydig cells respond to the gonadotropin LH to increase
androgen production. The response to LH, however, is
the initiation of a cascade of events in which androgens
can act on peritubular cells to promote PModS production that acts on Sertoli cells to influence functions
essential for germ cell development (Fig. 7). This androgen-mediated mesenchymal (stromal)-epithelial cell interaction may be similar in other androgen-dependent
organs during fetal development and in the adult (11, 22,
676). It is speculated that differentiation type factors
such as PModS may mediate steroid- or hormone-induced interactions in a wide variety of organs throughout
development. In addition to LH-induced cell-cell interactions, FSH actions on Sertoli cells also promote indirect effects on other testicular cell types. FSH will indirectly effect germinal cell development by altering Sertoli
cell-germinal cell interactions. Sertoli cells also appear
to produce FSH-dependent factors that can influence
Leydig cell function. Therefore, the two major endocrine
agents known to influence testis physiology act, in large
part, indirectly through alterations in local cellular interactions. Further investigation of the effects of endocrine agents on cell-cell interactions in the testis will be
required to elucidate male reproductive endocrinology.
The evolution of local cellular interactions that influence
tissue function under the control of the endocrine system
provides an efficient mechanism to regulate tissue physiology. The next era for the field of endocrinology will be
to elucidate how endocrine agents affect tissue function
on a molecular level through local cell-cell interactions.
C. Future directions
Information is needed on the paracrine and autocrine
factors that mediate testicular cell-cell interactions. Factors such as the peritubular cell-produced PModS,
growth factors such as SGF and SCSGF, and the Sertoli
cell-produced factors that influence Leydig cells need to
be more thoroughly purified and characterized on the
protein and molecular level. This is needed to identify
the unique or common properties of the factors as well
as provide reagents to further investigate the specific
cellular interactions. Two initial parameters to be considered in the analysis of cell-cell interactions are demonstration of the sites of production and action of regulatory agents. The expression of a specific gene and the
capacity of the cell to secrete the factor is one prerequisite for an agent to be involved in a local cellular interaction. Of equal importance is the demonstration of the
site of action of paracrine or autocrine factors. Regulatory factors must have defined and significant actions on
target cells to effect cellular growth, function, or differentiation. The majority of proposed cell-cell interactions
in the testis require further analysis on the cellular and
molecular level.
Elucidation of the biochemical properties of a potential
paracrine/autocrine agent and analysis of its site(s) of
production and actions in vitro, however, do not directly
address the physiological relevance of the proposed cellular interaction. The only testicular cell-cell interaction
that is known to be essential for testis function is the
need for the actions of androgen. Although androgens
are needed, the mode(s) of androgen actions remain to
be investigated. Few of the proposed cell-cell interactions
can be investigated thoroughly on a physiological level
at this time. As specific cell-cell interactions are elucidated it will be critical to determine the physiological
relevance and importance of these cellular interactions.
Acknowledgments
I thank Mary Couey, Karen Kerce, Lisa Halburnt, Jeff Parrott, and
Loretta Noisin for assistance in preparation of the manuscript, and Dr.
Bill Kovacs, Cathy Anthony, Andy Roberts, Brian Mullaney, and John
Norton for helpful comments on the manuscript.
References
1. Bernard C 1878 Sur les phenomenes de la vie. J. B. Balliere et
Fils, Paris
2. Bernard C 1927 An introduction to experimental medicine. Translation Green HC, introduction Henderson LJ, Macmillan, New
York, pp 1-226
3. Wilson HV 1907 On some phenomena of coalescence and regeneration in sponges. J Exp Zool 5:245
4. Steinberg MS 1963 Reconstruction of tissues by dissociated cells.
Some morphogenetic tissue movements and the sorting out of
embryonic cells may have a common explanation. Science 141:401
5. Spemann H 1938 Embryonic development and induction. Yale
University Press, New Haven, CT.
6. Tyler A 1946 An auto-antibody concept of cell structure, growth
and differentiation. Growth 10 (symposium 6):7
7. Weiss P 1947 The problem of specificity in growth and development. Yale J Biol Med 19:235
8. Grobstein C1967 Mechanisms of organogenetic tissue interaction.
Natl Cancer Inst Monogr 26:279
9. Roth S 1973 A molecular model for cell interactions. Q Rev Biol
48:541
10. Hood L, Huang HV, Dreyer WJ 1977 The area-code hypothesis:
the immune system provides clues to understanding the genetic
and molecular basis of cell recognition during development. J
Supramol Struct Cell Biochem 7:531
11. Cunha GR, Chung LWK, Shannon JM, Taguchi 0, Fujii H 1983
Hormone-induced morphogenesis and growth: role of mesenchymal-epithelial interactions. Recent Prog Horm Res 39:559
12. Trosko JE, Chang C, Madhukaar BV, Oh SY 1990 Chemical,
oncogene and growth regulatory modulation of extracellular, intracellular and intercellular communication. In: DeMello, WC
(ed) Cell Intercommunication. CRC Press, Cleveland, OH, pp 111
64
SKINNER
13. Pienta KJ, Partin AW, Coffey DS 1989 Cancer as a disease of
DNA organization and dynamic cell structure. Cancer Res 49:2525
14. Fidler IJ, Hart IR 1982 Biological diversity in metastatic neoplasms: origins and implications. Science 217:998
15. Greenberg ME, Brackenberry R, Edelman GM 1984 Alteration of
neural cell adhesion molecule (N-CAM) expression after neuronal
cell transformation by Rous sarcoma virus. Proc Natl Acad Sci
USA 81:969
16. Todaro GJ, Green H 1963 Quantitative studies of the growth of
mouse embryo cells in culture and their development into established lines. J Cell Biol 17:299
17. Pignatelli M, Bodmer WF 1988 Genetics and biochemistry of
collagen binding-triggered glandular differentiation in a human
colon carcinoma cell line. Proc Natl Acad Sci USA 85:5561
18. Marks PA, Sheffery M, Rifkind RA1987 Induction of transformed
cells to terminal differentiation and the modulation of gene
expression. Cancer Res 47:659
19. Bishop JM 1987 The molecular genetics of cancer. Science 235:305
20. Murphee AL, Benedict WF 1984 Retinoblastoma: clues to human
oncogenesis. Science 223:1028
21. Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert
JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW, Vogelstein B 1990 Identification of a chromosome 18q gene that is
altered in colorectal cancers. Science 247:49
22. Skinner MK 1987 Cell-cell interactions in the testis. Ann NY
Acad Sci 513:158
23. Spencer RF 1946 The cultural aspects of eunuchism. Ciba Symp
8:406
24. Derbes VJ 1970 The keepers of the bed. Castration and religion.
JAMA 212:97
25. Jocelyn HD, Setchell BP 1972 A treatise concerning the generative organs of men. An annotated translation of "Tractatus de
virorum organis generation inservientibus" 1668. J Reprod Fertil
[Suppl]17:l
26. Bremner WJ 1981 Historical aspects of the study of the testis. In:
Burger H and deKretser D (eds) The Testis. Raven, New York,
ppl-5
27. Baer CE von 1827 Beitrage zur kenntnis der niederen thiere. Nova
Acta Leopold Carol 13:640
28. Wagner R 1836 Die genesis der samenthierchen. Miiller's Arch
Anat Physiol 225
29. Wagner R 1839 Erlauterungstafeln zur physiologie und entwicklungsgeschichte. Voss, Leipzig.
30. Koelliker RA von 1841 Beitrage zur kenntris der geschlechtsverhaltnisse und der samenflussigkeit wirbelloser thiere. Berlin
31. Peter K1899 Die bedeutung der nahrzelle im hoden. Arch Mikrosk
Anat 53:180
32. Branca A 1923 Les can alicules testiculaures et al spematogenese
d l'homme. Etudes cytologiques. Arch Zool Exp Gen 62:53
33. Stieve H 1930 Mannliche genitalorgane. In: Mollendorf WV (ed)
Handbuch der mikro skopischen Anatomie des Menschen. J.
Springer, Berlin, 7(2) pp 1-142
34. Fawcett DW 1958 The structure of the mammalian spermatozoon.
Int Rev Cytol 7:195
35. de Krester DM 1969 Ultrastructural features of human spermiogenesis. Z Zellforsh Mikrosk Anat 98:477
36. Rowley MJ, Berlin JD, Heller CG 1971 The ultrastructure of four
types of human spermatogonia. Z Zellforsh Mikrosk Anat 112:461
37. Fawcett DW 1975 The ultrastructure and functions of the Sertoli
cell. In: Greep R, Hamilton E, Washington DC (eds) Handbook
of Physiology, sect 7, vol, 5, American Physiological Society,
Washington DC, pp 21
38. Russell LD, Clermont Y 1977 Degeneration of germ cells in
normal, hypophysectomized and hormone treated hypophysectomized rats. Anat Rec 187:3477
39. Holstein AF, Roosen-Runge EC 1981 Atlas of Human Spermatogenesis. Grosse Verlag, Berlin, pp 1-224
40. Rossen-Runge EC 1973 Germinal-cell loss in normal metazoan
spermatogenesis. J Reprod Fertil 35:339
41. Rossen-Runge EC 1977 The process of spermatogenesis in animals. Cambridge University Press, Cambridge, U.K.
Vol. 12, No. 1
42. Smith PE, Engle ET 1927 The disabilities caused by hypophysectomy and their repair. JAMA 88:158
43. Smith PE 1930 Hypophysectomy and a replacement therapy in
the rat. Am J Anat 45:205
44. Steinberger E, Steinberger A 1989 Hormonal control of spermatogenesis. In: DeGroot LJ (ed) Endocrinology. Saunders Co, Philadelphia, vol 3:2132
45. Griffin JE, Wilson JD 1985 Disorders of the testis and male
reproductive tract. In: Wilson JD, Foster DW (eds) Williams
Textbook of Endocrinology, ed. 7 Saunders Co, Philadelphia, p
259
46. Sar M, Stumpf WE, McLean WS, Smith AA, Hanson V, Nayfen
SN, French F 1975 Localization of androgen target cells in the
rat testis. Autoradiographic studies In: French FS, Hansson V,
Ritzen EM, Nayfon SN (eds) Hormonal Regulation of Spermatogenesis. Plenum Press, New York, p 311
47. Mulder E, Peters MJ, Van Beurden WMO, Galdieri M, Rommerts
FFG, Janzen FHA, vander Molen HJ 1976 Androgen receptors in
isolated cell preparations obtained from rat testicular tissue. J
Endocrinol 70:331
48. Sanborn BM, Steinberger A, Meistrich ML, Steinberger E 1975
Androgen binding sites in testis cell fractions as measured by a
nuclear exchange assay. J Steroid Biochem 6:1459
49. Hansson V, Djoseland O, Torgersen O, Ritzen EW, French FS,
Nayfeh SN 1976 Hormones and hormonal target cells in the
testis. Andrologia 8:195
50. Fritz IB 1978 Sites of action of androgens and follicle stimulating
hormone on cells of the seminiferous tubule. In: Litwack G (ed)
Biochemical Actions of Hormones. Academic Press, New York,
vol 5:249
51. Fritz IB 1984 Past, present and future of molecular and cellular,
endocrinology of the testis. INSERM Symp 123:15
52. Steinberger A, Steinberger E 1977 The Sertoli cell. In: Johnson
A, Gomes W (eds) The Testis. Academic Press, New York, vol
4:371-394
53. Tindall D, Rowley D, Murthy L, Lipschultz L, Chang C 1985
Structure and biochemistry of the Sertoli cell. Int Rev Cytol
94:127
54. Griswold MD 1988 Protein secretions of Sertoli cells. Int Rev
Cytol 110:133
55. Griswold MD, Morales C, Sylvester SR 1988 Molecular biology of
the Sertoli cell. Oxford Rev Reprod Biol 10:124
56. Bardin CW, Cheng CY, Musto NA, Gunsalus GL1988 The Sertoli
cell. In: Knobil E, Neill J (eds) The Physiology of Reproduction.
Raven Press Ltd, New York, vol 1:933-974
57. Setchell BP 1978 The Mammalian Testis. Cornell University
Press, Ithaca NY
58. Ritzen EM, Hansson V, French F 1989 The Sertoli cell. In: Burger
H, deKretser D (eds) The Testis, ed 2. Raven Press, New York,
P 269
59. Schulze C 1984 Sertoli cells and Leydig cells in man. Adv Anat
Embryol Cell Biol 88:1-104
60. Fritz IB, Rommerts FG, Louis BG, Dorrington JH 1976 Regulation of FSH and dibutyryl cyclic AMP of the formation of androgen-binding protein in Sertoli cell-enriched cultures. J Reprod
Fertil 46:17
61. Steinberger A, Heindel JJ, Lindsey JN, Elkington JSH, Sanborn
BM, Steinberger E 1975 Isolation and culture of FSH responsive
Sertoli cells. Endocr Res Commun 2:261
62. Hagenas L, Ritzen EM, Ploen L, Hansson V, French FS, Neyfeh
SN 1975 Sertoli cell origin of testicular androgen-binding protein
(ABP). Mol Cel Endocrinol 2:339
63. Skinner MK, Griswold MD 1980 Sertoli cells synthesize and
secrete a transferrin-like protein. J Biol Chem 255:9523
64. Skinner MK, Griswold MD 1983 Sertoli cells synthesize and
secrete a ceruloplasmin-like protein. Biol Reprod 28:1225
65. Kissinger C, Skinner MK, Griswold MD 1982 Analysis of Sertoli
cell secreted proteins by two-dimensional gel electrophoresis. Biol
Reprod 27:233
66. Sylvester SR, Skinner MK, Griswold MD 1984 A sulfated glycoprotein synthesized by Sertoli cells and by epididymal cells is a
component of the sperm membrane. Biol Reprod 31:1087
February, 1991
CELL-CELL INTERACTIONS IN THE TESTIS
67. Collard MW, Sylvester SR, Tsuruta JK, Griswold MD 1988
Biosynthesis and molecular cloning of sulfated glycoprotein 1
secreted by rat Sertoli cells: sequence similarity with the 70kilodalton precursor of sulfatide/GMl activator. Biochemistry
27:4557
68. O'Brien JS, Kretz KA, Dewji N, Wenger DA, Esch F, Fluharty
AL 1988 Coding of two sphingolipid activator proteins (SAP-1
and SAP-2) by same genetic locus. Science 241:1098
69. Kierszenbaum AL, Crowell JA, Shabinowitz RB, DePhilip RM,
Tres LL 1986 Protein secretory patterns of rat Sertoli and peritubular cells are influenced by culture conditions. Biol Reprod
35:239
70. Wilson RM, Griswold MD 1979 Secreted proteins from rat Sertoli
cells. Exp Cells Res 123:127
71. Cheng CY, Bardin CW 1986 Rat testicular testibumin is a protein
responsive to follicle stimulating hormone and testosterone that
shares immunodeterminants with albumin. Biochemistry 25:5276
72. Lacroix M, Smith FE, Fritz IB 1977 Secretion of plasminogen
activator by Sertoli cell enriched cultures. Mol Cell Endocrinol
9:227
73. Hettle JA, Waller EK, Fritz IB 1986 Hormonal stimulation alters
the type of plasminogen activator produced by Sertoli cells. Biol
Reprod 34:895
74. Dano K, Andreasen PA, Grondahl-Hansen J, Kristensen P, Nielsen LS, Skriver L 1985 Plasminogen activators, tissue degradation
and cancer. Adv Cancer Res 44:139
75. Wright WW, Luzarraga ML 1986 Isolation of cyclic protein-2
from rat seminiferous tubule fluid and Sertoli cell culture medium.
Biol Reprod 35:761
76. Wright WW, Parvinen M, Musto NA, Gunsalus GL, Phillips DM,
Mather JP, Bardin CW 1983 Identification of stage-specific proteins synthesized by rat seminiferous tubules. Biol Reprod 29:257
77. Erickson-Lawrence M, Zabludoff SD, Wright WW 1990 Cyclic
protein-2, a secretory product of rat Sertoli cells, is the proenzyme
form of cathepsin-L. J Cell Biol 111:107a
78. Cheng CY, Grima J, Stahler MS, Guglielmotti A, Silvestrini B,
Bardin CW 1990 Sertoli cell synthesizes and secretes a protease
inhibitor, a2-macroglobulin. Biochemistry 29:1063
79. Skinner MK, Tung PS, Fritz IB 1985 Cooperativity between
Sertoli cells and testicular peritubular cells in the production and
deposition of extracellular matrix components. J Cell Biol
100:1941
80. Skinner MK, Fritz IB 1985 Structural characterization of proteoglycans produced by testicular peritubular cells and Sertoli cells.
J Biol Chem 260:11874
81. Skinner MK, Takacs K, Coffey RJ 1989 Cellular localization of
transforming growth factor-alpha gene expression and action in
the seminiferous tubule: peritubular cell-Sertoli cell interactions.
Endocrinology 124:845
82. Skinner MK, Moses HL 1989 Transforming growth factor-beta
gene expression and action in the seminiferous tubule: peritubular
cell-Sertoli cell interactions. Mol Endocrinol 3:625
83. Hall K, Ritzen EM, Johnsonbaugh RE, Parvinen M 1983 Secretion of somatomedin-like compound from Sertoli cells in vitro. In:
Spencer EM (ed) Insulin-like Growth Factors/Somatomedins.
DeGruyter, New York, pp 611-614
84. Ritzen EM 1983 Chemical messengers between Sertoli cells and
neighboring cells. J Steroid Biochem 19:499
85. Tres LL, Smith EP, Van Wyk JJ, Kierzenbaum AL 1986 Immunoreactive sites and accumulation of somatomedin-C in rat Sertoli-spermatogenic cell co-cultures. Exp Cell Res 162:33
86. Smith EP, Svoboda ME, Van Wyk JJ, Kierszenbaum AL, Tres
LL 1987 Partial characterization of a somatomedin-like peptide
from the medium of cultured rat Sertoli cells. Endocrinology
120:186
87. Holmes SD, Spotts G, Smith RG 1986 Rat Sertoli cells secrete a
growth factor that blocks epidermal growth factor (EGF) binding
to its receptor. J Biol Chem 261:4076
88. Khan SA, Soder O, Syed V, Gustafsson K, Lindh M, Ritzen EM
1987 The rat produces large amounts of an interleykin-1-like
factor. Int J Androl 10:495
65
89. Robinson R, Fritz IB 1981 Metabolism of glucose by Sertoli cells
in culture. Biol Reprod 24:1032
90. Jutte NHPM, Grootegoed JA, Rommerts FFG, van der Molen HJ
1981 Exogenous lactate is essential for metabolic activities in
isolated rat spermatocytes and spermatids. J Reprod Fertil 62:399
91. Jutte NHPM, Jansen R, Grootegoed JA, Rommerts FFG, van der
Molen HJ 1983 FSH stimulation of the production of pyruvate
and lactate by rat Sertoli cells may be involved in hormonal
regulation of spermatogenesis. J Reprod Fertil 68:219
92. Dorrington JH, Fritz IB, Armstrong DT 1978 Control of testicular
estrogen synthesis. Biol Reprod 18:55
93. deJong FH, Robertson DM 1985 Inhibin: 1985 update on action
and purification. Mol Cell Endocrinol 42:95
94. Josso N, Picard JY 1986 Anti-mullerian hormone. Physiol Rev
66:1038
95. Griswold MD, Roberts K, Bishop P 1986 Purification and characterization of a sulfated glycoprotein secreted by Sertoli cells.
Biochemistry 25:7265
96. Collard MW, Griswold MD 1987 Biosynthesis and molecular
cloning of sulfated glycoprotein-2 secreted by rat Sertoli cells.
Biochemistry 26:3297
97. Jenne DE, Tschopp J 1989 Molecular structure and functional
characterization of a human complement cytolysis inhibitor found
in blood and seminal plasma: identity to sulfated glycoprotein 2,
a constituent of rat testis fluid. Proc Natl Acad Sci USA 86:7123
98. Wyatt CR, Law L, Magnuson JA, Griswold MD, Magnuson NS
1988 Suppression of lymphocyte proliferation by proteins secreted
by cultured Sertoli cells. J Reprod Immunol 14:27
99. Blaschuk O, Burdzy K, Fritz IB 1983 Purification and characterization of a cell-aggregating factor (clusterin), the major glycoprotein in ram rete testis fluid. J Biol Chem 258:7714
100. Blaschuk O, Fritz IB 1984 Isoelectric forms of clusterin isolated
from ram rete testis fluid and from secretions of primary cultures
of ram and rat Sertoli cell enriched cultures. Can J Biochem Cell
Biol 62:456
101. Cheng CY, Chen CL, Feng ZM, Marshall A, Bardin CW 1988 Rat
clusterin isolated from primary Sertoli cell enriched culture medium is sulfated glycoprotein-2 (SGP-2). Biochem Biophys Res
Commun 155:398
102. Cheng CY, Mather JP, Byer AL, Bardin CW 1986 Identification
of hormonally responsive proteins in primary Sertoli cell-culture
medium by anion exchange high performance liquid chromatography. Endocrinology 118:480
103. Walsh EL, Cuyler WK, McCullagh DR 1933 Effect of testicular
hormone on hypophysectomized rats. Proc NY Soc Exp Biol Med
50:848
104. Walsh EL, Cuyler WK, McCullagh DR 1934 Physiologic maintenance of male sex glands: effect of androtin on hypophysectomized
rats. Am J Physiol 107:508
105. Odell WD 1989 The Leydig cell. In: LJ DeGroot (ed) Endocrinology. Saunders Co, Philadelphia, p 2137
106. Ascoli M 1985 Leutinizing Hormone Receptors and Actions, CRC
Press, Boca Raton FL
107. Odell WD 1976 Etiologies of sexual maturation: a model system
based on the sexually maturing rat. Recent Prog Horm Res 32:245
108. Margioris AN, Liotta A, Vaudry H, Bardin CW, Krieger DT 1983
Characterization of immunoreactive proopiomelanocortin-related
peptides in rat testis. Endocrinology 113:663
109. Melner MH, Puett D 1984 Evidence for synthesis of multiple proopiomelanocortin-like precursors in murine Leydig tumor cells.
Arch Biochem Biophys 232:197
110. Tsong S-D, Phillips DM, Halmi N, Krieger D, Bardin CW 1982
/3-Endorphin is present in the male reproductive tract on five
species. Biol Reprod 27:755
111. Chen C, Mather JP, Morris PL, Bardin CW 1984 Expression of
pro-opiomelanocortin-like gene in the testis and epididymis. Proc
Natl Acad Sci USA 81:5672
112. Pintar JE, Schachter BS, Herman AB, Durgerian S, Krieger DT
1984 Characterization and localization of proopiomelanocortin
messenger RNA in the adult rat testis. Science 225:632
113. Risbridger GP, Clements J, Robertson DM, Drummond AE, Muir
J, Berger HG, de Kretser DM 1989 Immuno- and bioactive inhibin
66
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
SKINNER
and inhibin alpha-subunit expression in rat Leydig cell cultures.
Mol Cell Endocrinol 66:119
Cailleau J, Vermeire S, Verhoeven G 1990 Independent control of
the production of insulin-like growth factor I and its binding
protein by cultured testicular cells. Mol Cell Endocrinol 69:79
Tung PS, Skinner MK, Fritz IB 1984 Fibronectin synthesis is a
marker for peritubular cell contaminants in Seroli-enriched cultures. Biol Reprod 30:199
Skinner MK, Stallard B, Anthony CT, Griswold MD 1989 Cellular
localization of fibronectin gene expression in the seminiferous
tubule. Mol Cell Endocrinol 66:45
Skinner MK, Fritz IB 1985 Testicular peritubular cells secrete a
protein under androgen control that modulates Sertoli cell function. Proc Natl Acad Sci USA 82:114
Skinner MK, Fetterolf PM, Anthony CT 1988 Purification of a
paracrine factor, PModS, produced by testicular peritubular cells
that modulates Sertoli cell function. J Biol Chem 263:2884
Norton JN, Skinner MK 1989 Regulation of Sertoli cell function
and differentiation through the actions of a testicular paracrine
factor PModS. Endocrinology 124:2711
Hettle JA, Balekjian E, Tung PS, Fritz IB 1988 Rat testicular
peritubular cells in culture secrete an inhibitor of plasminogen
activator activity. Biol Reprod 38:359
Sato G 1979 The growth of cells in germ-free hormone-supplemented medium. In: Jakoby WB, Pastan IH (eds) Methods in
Enzymology. Academic Press, New York, pp 94-109
Ham RG, McKeehan WL 1979 Media and growth requirements.
In: Jakoby WB, Pastan IH (eds) Methods in Enzymology. Academic Press, New York, pp 44-93
Hsueh AJW, Adashi EY, Jones PBC, Welsh TH 1984 Hormonal
regulation of the differentiation of cultured ovarian granulosa
cells. Endocr Rev 5:76
Kodani M, Kodani K 1966 The in vitro culturation of mammalian
Sertoli cells. Proc Natl Acad Sci USA 56:1200
Steinberger E, Steinberger A, Perloff WH 1964 Studies on growth
in organ culture of testicular tissue from rats of various ages. Anat
Rec 148:581
Steinberger E, Steinberger A, Ficher M 1970 Study of spermatogenesis and steroid metabolism in cultures of mammalian testes.
Recent Prog Horm Res 26:547
Janszen FHA, Cooke BA, van Driel MJA, van der Molen HJ 1976
Purification and characterization of Leydig cells from rat testis.
J Endocrinol 70:345
Conn PM, Tsuruhara T, Dafau ML, Catt KJ 1977 Isolation of
highly purified Leydig cells by density gradient centrifugation.
Endocrinology 101:639
Payne AH, Downing JR, Wong KL 1980 Luteinizing hormone
receptors and testosterone synthesis in two distinct populations
of Leydig cells. Endocrinology 106:1424
Browning JY, D'Agata R, Grotjan Jr HE 1981 Isolation of purified
rat Leydig cells using continuous Percoll gradients. Endocrinology
109:667
Cooke BA, Magee-Brown R, Golding M, Dix CJ 1981 The heterogeneity of Leydig cells from mouse and rat testes: evidence for a
Leydig cell cycle? Int J Androl 4:355
Gale JS, Wakefield J, Ford HC 1982 Isolation of rat Leydig cells
by density gradient centrifugation. J Endocrinol 92:293
Schumacher M, Schafer G, Holstein AF, Hilz H 1978 Rapid
isolation of mouse Leydig cells by centrifugation in Percoll density
gradients with complete retention of morphological and biochemical integrity. FEBS Lett 91:333
Kerr JB, Robertson DM, deKretser DM 1985 Morphological and
functional characterization of interstitial cells from mouse testes
fractionated on Percoll density gradients. Endocrinology 116:1030
Lam DMK, Furrer R, Bruce WR 1970 The separation, physical
characterization and differentiation kinetics of spermatogonial
cells of the mouse. Proc Natl Acad Sci USA 65:192
Go VLM, Vernon RG, Fritz IB 1971 Studies on spermatogenesis
in rats. I. Application of the sedimentation velocity technique to
an investigation of spermatogenesis. Can J Biochem 49:753
Loir M, Lanneau M 1974 Separation of ram spermatids by sedimentation at unit gravity. Exp Cell Res 83:319
Vol. 12, No. 1
138. Meistrich ML 1972 Separation of mouse spermatogenic cells by
sedimentation velocity. J Cell Physiol 80:299
139. Meistrich ML, Bruce WR, Clermont Y 1973 Cellular composition
of mouse testis cells following velocity sedimentation separation.
Exp Cell Res 79:213
140. Davis JC, Schuetz AW 1975 Separation of germinal cells from
immature rat testes by sedimentation at unit gravity. Exp Cell
Res 91:79
141. Romrell LJ, Bellve' AR, Fawcett DW 1976 Separation of mouse
spermatogenic cells by sedimentation velocity: a morphological
characterization. Dev Biol 49:119
142. Bellve' AR, Millette CF, Bhatnagar YM, O'Brien DA 1977 Dissociation of the mouse testis and characterization of isolated
spermatogenic cells. J Histochem Cytochem 25:480
143. Bellve' AR, Cavicchia JC, Millette CF, O'Brien DA, Bhatnagar
YM, Dym M 1977 Spermatogenic cells of the prepuberal mouse
(isolation and morphological characterization). J Cell Biol 74:68
144. Meistrich ML, Longtin J, Brock WA, Grimes SR, Mace ML 1981
Purification of rat spermatogenic cells and preliminary biochemical analysis of these cells. Biol Reprod 25:1065
145. Stern L, Gold B, Hecht NB 1983 Gene expression during mammalian spermatogenesis. I. Evidence for stage-specific synthesis
of polypeptides in vivo. Biol Reprod 28:483
146. Risley M 1983 Spermatogenic cell differentiation in vitro. Gamete
Res 4:331
147. Dorrington JH, Fritz IB 1975 Cellular localization of 5a-reductase
and 3a-hydroxysteroid dehydrogenase in the seminiferous tubule
of the rat testis. Endocrinology 96:879
148. Dorrington JH, Roller NF, Fritz IB 1975 Effects of folliclestimulating hormone on cultures of Sertoli cell preparations. Mol
Cell Endocrinol 3:57
149. Steinberger A, Heindel JJ, Lindsey JN, Elkington JSH, Sanborn
BM, Steinberger E 1975 Isolation and culture of FSH responsive
Sertoli cells. Endocr Res Commun 2:261
150. Steinberger A, Elkington JSH, Sanborn BM, Steinberger E, Heindel JJ, Lindsey JN 1975 In: French FS, Hansson V, Ritzen EM,
Nayfeh S (eds) Hormonal Regulation of Spermatogenesis. Plenum
Press, New York, pp 399-411
151. Welsh MJ, Wiebe JP 1975 Rat Sertoli cells: a rapid method for
obtaining viable cells. Endocrinology 96:618
152. Tung PS, Dorrington JH, Fritz IB 1975 Structural changes induced by follicle-stimulating hormone or dibutyryl cyclic AMP
on presumptive Sertoli cells in culture. Proc Natl Acad Sci USA
72:1838
153. Fritz IB, Louis BG, Tung PS, Griswold MD, Rommerts FG,
Dorrington JH 1975 In: French FS, Hansson V, Ritzen EM,
Nayfeh S (eds) Hormonal Regulation of Spermatogenesis. Plenum
Press, New York, pp 367-382
154. Galdieri M, Ziparo E, Palombi F, Russo MA, Stefanini MJ 1981
Pure Sertoli cell cultures: a new model for the study of somaticgerm cell interactions. J Androl 2:249
155. Wagle JR, Heindel JJ, Steinberger A, Sanborn BM 1986 The
effect of hypotonic treatment on Sertoli cell purity and cell
function in culture. In Vitro 22:325
156. Tung PS, Lacroix M, Fritz IB 1980 Effects of cytosine arabinoside
on properties of testicular preparations in culture. Biol Reprod
22:1255
157. Gilmont RR, Coulter GH, Sylvester SR, Griswold MD 1990 Synthesis of transferrin and transferrin mRNA in bovine Sertoli cells
in culture and in vivo: sequence and partial cDNA clone for
bovine transferrin. Biol Reprod 43:139
158. Perrard-Sapori MH, Saez JM, Dazord A 1985 Hormonal regulation of proteins secreted by cultured pig Sertoli cells: characterization by two-dimensional polyacrylamide gel electrophoresis.
Mol Cell Endocrinol 43:189
159. Keeping HS, Winters SJ, Troen P 1985 Identification of androgen-binding protein from testis cytosol and Sertoli cell culture
medium of the Cynomolgus monkey, Macaca fascicularis. Endocrinology 117:1521
160. Lipschultz LI, Murthy L, Tindall DJ 1982 Characterization of
human Sertoli cells in vitro. J Clin Endocrinol Metab 55:228
161. Anthony CT, Skinner MK 1989 Cytochemical and biochemical
February, 1991
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
185.
186.
CELL-CELL INTERACTIONS IN THE TESTIS
characterization of testicular peritubular (myoid) cells. Biol Reprod 40:811
Tung PS, Fritz IB 1990 Characterization of rat testicular peritubular myoid cells in culture: a-smooth muscle isoactin is a specific
differentiation marker. Biol Reprod 42:351
Tung PS, Fritz IB 1977 Isolation and culture of testicular cells. A
morphology at characterization. In: Hafez ESE (ed) Techniques
of Human Andrology. North Holland, Amsterdam, pp 125-146
Polombi F, DiCarlo C 1988 Alkaline phosphatase is a marker for
myoid cells in cultures of rat peritubular and tubular tissue. Biol
Reprod 39:1101
Chapin RE, Phelps JL, Miller BE, Gray TJB 19$7 Alkaline
phosphatase histochemistry discriminates peritubular cells in primary rat testicular cell culture. J Androl 8:155
Virtanen I, Kallajoki M, Narvanen 0, Paranko J, Thornell L-E,
Miettinen M, Lento V-P 1986 Peritubular myoid cells of human
and rat testis are smooth muscle cells that contain desmin-type
intermediate filaments. Anat Rec 215:10
Mather JP 1980 Establishment and characterization of two distinct mouse testicular epithelial cell lines. Biol Reprod 23:243
Mather JP, Zhuang L, Perez-Infante V, Philips DM 1982 Culture
of testicular cells in hormone-supplemented serum-free medium.
Ann NY Acad Sci 383:44
Ascoli M 1981 Characterization of several clonal lines of cultured
Leydig tumor cells: gonadotropin receptors and steroidogenic
responses. Endocrinology 108:88
Russell LD, Steinberger A 1989 Sertoli cells in culture: views from
the perspectives of an in vivoist and an in vitroist. Biol Reprod
41:571
Eagle H 1965 Growth regulatory effects of cellular interactions.
Israel J Med Sci 1:1220
Sharpe RM 1984 Intratesticular factors controlling testicular
function. Biol Reprod 30:29
Sharpe RM 1986 Paracrine control of testis. Clin Endocrinol
Metab 15:185
Findlay JK, Risbridger GP 1987 Intragonadal control mechanisms. Baillieres Clin Endocrinol Metab 1:223
Saez JM, Perrard-Sapori MH, Chatelain PG, Tabone E, Rivarola
MA 1987 Paracrine regulation of testicular function. J Steroid
Biochem 27:317
Demoulin A, Frenchimont P 1989 Paracrine regulation of testicular function. Acta Urol Belg 57:47
Fritz IB, Skinner MK, Tung PS 1986 The nature of somatic cell
interactions in the seminiferous tubule. In: Eshkol A, Eckstein B,
Dekel N, Peterson H, Tsafriri A (eds) Development and function
of reproductive organs. Cristengraf Publishers, Rome, p 185
Fritz IB, Tung PS 1986 Role of interactions between peritubular
cells and Sertoli cells in mammalian testicular function. Gametogenesis and Early Embryo. Alan Liss Inc, New York p 151
Fritz IB 1985 Reflections on the evolution of the regulation of
spermatogenesis. In: Sato G, Serraro G, Hayashi J (eds) International Symposium on Cellular Endocrinology. Alan Liss Publishers, New York, p 1
Fritz IB, Tung PS 1986 Testicular peritubular cell-Sertoli cell
interactions. In: Stefanini M, Conti M, Geremia R, Ziparo E (eds)
Molecular and Cellular Endocrinology of the Testis. Excerpta
Medica, Amsterdam NY, p 27
Closset J, Dombrowicz D, Vandenbroeck M, Scippo ML, Igout A,
Gothot A, Sente B, Hennen G 1989 Endocrine, paracrine and
autocrine factors in the maturation and functional development
of the testis. Bull Mem Acad R Med Belg 144:188
Grootegoed JA, Den Boer PJ, Mackenbach P 1989 Sertoli cellgerm cell communication. Ann NY Acad Sci 564:232
Saez JM, Avallet O, Naville D, Perrard-Sapori MH, Chatelain
PG 1989 Sertoli-Leydig cell communications. Ann Ny Acad Sci
564:210
Rommerts FF, Brinkman AO 1981 Modulation of steroidogenic
activities in testis Leydig cells. Mol Cell Endocrinol 21:15
Sharpe RM, Fraser HM, Cooper I, Rommerts FF 1982 The
secretion, measurement and function of a testicular LHRH-like
factor. Ann NY Acad Sci 383:272
Risbridger GP, deKretser DM 1989 Paracrine regulation of the
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
67
testis. In: Burger H, deKretser DM (eds) The Testis, 2 ed. Raven
Press Ltd New York, p 255
Parvinen M, Vihko KK, Toppari J 1986 Cell interactions during
the seminiferous epithelial cycle. Int Rev Cytol 104:115
Skinner MK 1989 Peritubular myoid cell-Sertoli cell interactions
which regulate testis function and growth. Perspect Androl 53:175
Fabbri A, Ulisse S, Bolotti M, Ridolfi M, Spera G, Dufau ML,
Isidori A 1989 Opioid regulation of testicular function. Perspect
Androl 53:203
Soder O, Pollanen P, Syed U, Hoist M, Granholm K, Arver S,
Euler M, Gustafsson K, Froysa B, Parvinen M, Ritzen EM 1989
Perspect Androl 53:215
de Kretser DM 1987 Local regulation of testicular function. Int
Rev Cytol 109:89
Koelliker RA von 1899 Erinnerungen aus meinem Leben. W.
Engelmann, Leipzig.
Sertoli E 1865 On the existence of special branched cells in the
seminiferous tubules of the human testis. Morgagni 7:31
Clermont 1972 Kinetics of spermatogenesis in mammals: seminiferous epithelial cycle and spermatogonial renewal. Physiol Rev
52:198
Bellve' AR 1979 The molecular biology of mammalian spermatogenesis. In: CA Finn (ed) Oxford Reviews of Reproductive Biology,
vol 1. Calendron Press, Oxford, pp 159-261
Russell LD, Alger LE, Nequin LG 1987 Hormonal control of
pubertal spermatogenesis. Endocrinology 120:1204
Brokelmann J 1963 Fine structure of germ cells and Sertoli cells
during the cycle of the seminiferous epithelium in the rat. Z
Zellforsch Mikrosk Anat 59:820
Nicander L 1967 An electron microscopical study of cell contacts
in the seminiferous tubules of some mammals. Z Zellforsch Mikrosk Anat 83:375
Flickinger C, Fawcett DW 1967 The junctional specializations of
Sertoli cells in the seminiferous epithelium. Anat Rec 158:207
Dym M, Fawcett DW 1970 The blood-testis barrier in the rat and
the physiological compartmentation of the seminiferous epithelium. Biol Reprod 3:308
Dym M 1972 The fine structure of the monkey Sertoli cell and its
role in establishing the blood-testis fluid barrier. Biol Reprod
7:129a
202. Aoki A, Fawcett DW 1975 Impermeability of Sertoli cell junctions
to prolonged exposure to peroxidase. Andrologia 7:63
203. Setchell BP 1960 Do the Sertoli cells secrete the rete testis fluid?
J Reprod Fertil 19:391
204. Setchell BP 1967 The blood-testicular fluid barrier in sheep. J
Physiol (Lond) 189:63
205. Tuck RR, Setchell BP, Waites GM, Young JA 1970 The composition of fluid collected by micropuncture and catheterization from
the seminiferous tubules and rete testis of rats. Pflueger Arch
318:225
206. Waites GMH 1977 Fluid secretion. In: Johnson A, Gomes W (eds)
The Testis, vol 4. Academic Press, New York, 91-123
207. Setchell BP 1980 The functional significance of the blood-testis
barrier. Andrology 1:3
208. Ross MH 1976 The Sertoli cell junctional specialization during
spermiogenesis and at spermiation. Anat Rec 186:79
209. Russell LD, Clermont Y 1976 Anchoring device between Sertoli
cells and late spermatids in rat seminiferous tubules. Anat Rec
185:259
210. Russell L 1977 Desmosome-like junctions between Sertoli and
germ cells in the rat testis. Am J Anat 148:301
211. Franke WD, Grund C, Fink A, Weber K, Jockush BM, Zentgraf
H, Osborn M 1978 Location of actin in the microfilament bundles
associated with the junctional specializations between Sertoli cells
and spermatids. Biol Cell 31:7
212. Russell LD, Tallon-Doran M, Weber JE, Wong V, Peterson RN
1983 Three-dimensional reconstruction of a rat stage V Sertoli
cell. III. A study of specific cellular relationships. Am J Anat
167:181
213. Vogl AW, Soucy LJ 1985 Arrangement and possible function of
actin filament bundles in ectoplasmic specializations of ground
squirrel Sertoli cells. J Cell Biol 100:814
68
SKINNER
214. Grove BD, Vogl AW 1986 Sertoli cell ectoplasmic specializations:
a type of actin-associated adhesion junction? J Cell Sci 93:309
215. Fawcett DW, Phillips DM 1969 Observations on the release of
spermatozoa and on changes in the head during passage through
the epididymis. J Reprod Fertil [Suppl]6:405
216. Russell LD 1979 Further observations on tubulobulbar complexes
formed by late spermatids and Sertoli cells in the rat testis. Anat
Rec 194:213
217. Malone J 1979 A study of Sertoli spermatid tubulobulbar complexes in selected mammals. Anat Rec 193:610
218. Russell LD 1978 Testosterone induced deformities in rat spermiogenesis: failure of tubulobulbar complexes to form in late spermatids. Anat Rec 190:527
219. Gravis CJ 1979 Inhibition of spermiation in the Syrian hamster
using dibutyryl cAMP. Cell Tissue Res 192:241
220. Clermont Y, McCoshen J, Hermo L 1980 Evolution of the endoplastic reticulum in Sertoli cell cytoplasm encapsulating the head
of late spermatids in the rat. Anat Rec 196:83
221. Wong V, Russell LD 1983 Three dimensional reconstruction of a
rat stage V Sertoli cell. I. Methods, basic configuration and
dimensions. Am J Anat 167:143
222. Weber JE, Russell LD, Wong V, Peterson RN 1983 Three dimensional reconstruction of a rat stage V Sertoli cell. II. Morphometry
of Sertoli-Sertoli and Sertoli-germ-cell relationships. Am J Anat
167:163
223. Clermont Y 1972 Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonial renewal. Physiol
Rev 52:198
224. Leblond CP, Clermont Y 1952 Definition of the stages of the cycle
of the seminiferous epithelium in the rat. Ann NY Acad Sci 55:548
225. Kerr JB, deKretser DM 1975 Cyclic variations in Sertoli cell lipid
content throughout the spermatogenic cycle of the rat. J Reprod
Fertil 43:1
226. Hilscher B, Passia D, Hilscher W 1979 Kinetics of the enzymatic
pattern in the testis. I. Stage dependence of enzymatic activity
and its relation to cellular interactions in the testis of the Wistar
rat. Andrologia 11:169
227. Morales C, Clermont Y, Nadler NJ 1986 Cyclic endocytic activity
and kinetics of lysosomes in Sertoli cells of the rat: a morphometric analysis. Biol Reprod 34:207
228. Johnson L, Amann RP, Pickett BW 1978 Scanning electrons and
light microscopy of the equine seminiferous tubule. Fertil Steril
29:208
229. Cavicchia JC, Dym M 1977 Relative volume changes of Sertoli
cells in monkey seminiferous epithelium: a stereological analysis.
Am J Anat 150:501
230. Bugge HP, Ploen L 1986 Changes in the volume of Sertoli cells
during the cycle of the seminiferous epithelium in the rat. J
Reprod Fertil 76:39
231. Niemi M, Kormano M 1965 Cyclical changes in and significance
of lipids and acid phosphatase activity in the seminiferous tubules
of the rat testis. Anat Rec 151:159
232. Posalaki Z, Szabo D, Basci E, Okros I 1968 Hydrolytic enzymes
during spermatogenesis in rat. An electron microscopic and histochemical study. J Histochem Cytochem 16:249
233. Parvinen M, Vanha-Perttula T 1972 Identification and enzyme
quantitation of the stages of the seminiferous epithelial wave in
the rat. Anat Rec 174:435
234. Parvinen M, Hecht NB 1981 Identification of living spermatogenic cells of the mouse by transillumination-phase contrast
microscopic technique for 'in situ' analyses of DNA polymerase
activities. Histochemistry 71:567
235. Nikkanen U, Soderstrom KO, Parvinen M 1978 Identification of
the spermatogenic stages of living seminiferous tubules of man. J
Reprod Fertil 53:255
236. Mason KE 1933 Differences in testes injury and repair after
vitamin A deficiency, vitamin E deficiency and inanition. Am J
Anat 52:153
237. Thompson JN, Howell JM, Pitt GA 1964 vitamin A and reproduction in rats. Proc R Soc Lond B Biol 159:510
238. Huang HF, Hembree WC 1979 Spermatogenic response to vitamin
A in vitamin A deficient rats. Biol Reprod 21:891
Vol. 12, No. 1
239. Huang HF, Dyrenfurth I, Hembree WC 1983 Endocrine changes
associated with germ cell loss during vitamin A induced recovery
of spermatogenesis. Endocrinology 112:1163
240. Morales C, Hugly S, Griswold MD 1987 Stage dependent levels
of specific mRNA transcripts in Sertoli cells. Biol Reprod 36:1035
241. Morales C, Griswold MD 1987 Retinol-induced stage synchronization in seminiferous tubules of the rat. Endocrinology 121:432
242. Bartlett JMS, Weinbauer GF, Nieschlag E 1990 Stability of
spermatogenic synchromilization achieved by depletion and restoration of vitamin A in rats. Biol Reprod 42:603
243. VanPelt AMM, DeRooij DG 1990 The origin of the synchrounization of the seminiferous epithelium in vitamin A-deficient rats
after vitamin A replacement. Biol Reprod 42:677
244. Russell L 1977 Movement of spermatocytes from the basal to the
adluminal compartment of the rat testis. Am J Anat 148:313
245. Russell LD 1978 The blood-testis barrier and its formation relative to spermatocyte maturation in the adult rat: a lanthanum
tracer study. Anat Rec 190:99
246. Lacroix M, Parvinen M, Fritz IB 1981 Localization of testicular
plasminogen activator in discrete proteins (stages VII and VIII)
of the seminiferous tubule. Biol Reprod 25:143
247. Fritz IB, Karmally K 1983 Hormonal influences on formation of
plasminogen activator by cultured testis tubule segments at defined stages of the cycle of the seminiferous epithelium. Can J
Biochem Cell Biol 61:553
248. Ailenberg M, McCabe D, Fritz IB 1990 Androgens inhibit plasminogen activator activity secreted by Sertoli cells in culture in a
two-chambered assembly. Endocrinology 126:1561
249. Wright WW, Zabludoff SD, Erickson-Lawrence M, Karzai AW
1989 Germ cell-Sertoli cell interactions. Studies of cyclic protein2 in the seminiferous tubule. Ann NY Acad Sci 564:173
250. Ross MH, Dobler J 1975 The Sertoli cell junctional specializations
and their relationship to the germinal epithelium as observed
after efferent ductule ligation. Anat Rec 183:267
251. Ulvik NM 1984 Lamellar germ cell processes: structures for
possible interaction between germ cells and Sertoli cells during
spermatogonial differentiation and early meiotic prophase. Int J
Androl 7:129
252. Eddy EM, Kahri AI1976 Cell association and surface features in
cultures of juvenile rat seminiferous tubules. Anat Rec 185:333
253. Tres LL, Kierszenbaum AL 1983 Viability of rat spermatogenic
cells in vitro is facilitated by their coculture with Sertoli cells in
serum-free hormone-supplemented medium. Proc Natl Acad Sci
USA 80:3377
254. DePhilip RM, Danahey DG 1987 Germ cell binding to rat Sertoli
cells in vitro. Biol Reprod 37:1271
255. D'Agostino A, Stefanini M 1987 A rat spermatocyte surface protein is involved in adhesion of pachytene spermatocytes to Sertoli
cells in vitro. Mol Cell Biol 7:1250
256. D'Agostino A, Monaco L, Stefanini M, Geremia R 1984 Study of
the interaction between germ cells and Sertoli cells in vitro. Exp
Cell Res 150:430
257. Zani BM, Ziparo E, Russo MA, Filippini A, Stefanini M 1987
Membrane molecules involved in adhesion properties of cultured
Sertoli cells. Gamete Res 18:301
258. Russell LD 1984 Spermiation-the sperm release process: ultrastructural observations and unresolved problems. In: Blerkom J
Van, Motta PM (eds) Electron Microscopy in Biology and Medicine. Ultrastructure of Reproduction. Martinus Nijhoff Publishers, Boston, pp 46-65
259. Millette CF, Bellve' AR 1985 Selective partitioning of plasma
membrane antigens during mouse spermatogenesis. Dev Biol
79:309
260. Waites GM, Gladwell RT 1982 Physiological significance of fluid
secretion in the testis and blood-testis barrier. Physiol Rev 62:624
261. Christensen AK, Komorowski TE, Wilson B, Ma SF, Stevens
RW 1985 The distribution of serum albumin in the rat testis,
studied by electron microscope immunocytochemistry or ultrathin
frozen sections. Endocrinology 116:1983
262. Nagano T, Suzuki F 1978 Cell to cell relationships in the seminiferous epithelium in the mouse embryo. Cell Tissue Res 189:389
263. Pelletier RM, Friend DS 1983 The Sertoli cell junctional complex:
February, 1991
CELL-CELL INTERACTIONS IN THE TESTIS
structure and permeability to filipin in the neonatal and adult
guinea pig. Am J Anat 168:213
264. McGinley DM, Posalaky Z 1986 Gap junctions between gonocytes
and epithelial cells in the sex cords of the one day old rat. A freeze
fracture study. J Submicrosc Cytol 18:75
265. De Felici M, Dolci S, Siracusa G 1989 Fetal germ cells establish
cell coupling with follicle cells in vitro. Cell Differ Dev 28:65
266. Russell LD 1977 Observations on rat Sertoli ectoplasmic ("junctional") specializations in their association with germ cells of the
rat testis. Tissue Cell 9:475
267. McGinley DM, Posalaky Z, Porvaznik M, Russell LD 1979 Gap
junctions between Sertoli cells and germ cells of rat seminiferous
tubules. Tissue Cell 11:741
268. Ziparo E, Siracusa G, Palombi F, Russo MA, Stefanini M 1982
Formation in vitro of intercellular junctions between isolated germ
cells and Sertoli cells in the rat. Ann NY Acad Sci 383:511
269. Gravis CJ, Yates RD, Chen IL 1976 Light and electron microscopic localization of ATPase in normal and degenerating testes
of Syrian hamsters. Am J Anat 147:419
270. Robinson R, Fritz IB 1979 Myoinositol biosynthesis by Sertoli
cells, and levels of myoinositol biosynthetic enzymes in testis and
epididymis. Can J Biochem 57:962
271. Grootegoed JA, Oonk RB, Jansen R, van der Molen HJ 1986
Metabolism of radiolabelled energy-yielding substrates by rat
Sertoli cells. J Reprod Fertil 77:109
272. Mita M, Price JM, Hall PF 1982 Stimulation by FSH of synthesis
of lactate by Sertoli cells from rat testis. Endocrinology 110:1535
273. Yee JB, Hutson JC 1989 Follicle-stimulating hormone-induced
lactate secretion by cultured Sertoli cells does not require extracellular calcium. Life Sci 44:1193
274. Oonk RB, Jansen R, Grootegoed JA 1989 Differential effects of
follicle-stimulating hormone, insulin, and insulin-like growth factor I on hexose uptake and lactate production by rat Sertoli cells.
J Cell Physiol 139:210
275. Boitani C, Palombi F, Stefanini M 1983 Influence of Sertoli cell
products upon the in vitro survival of isolated spermatocytes and
spermatids. Cell Biol Int Rep 7:383
276. Mita M, Hall PF 1982 Metabolism of round spermatids from rats
lactate as the preferred substrate. Biol Reprod 26:445
277. Risley MS 1990 Support of Xenopus laevis spermatogenesis in
vitro by different energy substrates. Biol Reprod 42:511
278. Santiemma V, Salfi V, Casasanta N, Fabbrini A 1987 Lactate
dehydrogenase and malate dehydrogenase of Sertoli cells in rats.
Arch Androl 19:59
279. Hall PF, Mita M 1984 Influence of FSH on glucose transport by
cultured Sertoli cells. Biol Reprod 31:863
280. Gunsalus GL, Musto NA, Bardin W 1978 Immunoassay of androgen binding protein in blood: a new approach for study of the
seminiferous tubule. Science 200:65
281. Aisen P, Listowsky I 1980 Iron transport and storage proteins.
Annu Rev Biochem 49:357
282. Skinner MK, Cosand WL, Griswold MD 1984 Purification and
characterization of testicular transferrin secreted by rat Sertoli
cells. Biochem J 218:313
283. Huggenvik JI, Idzerda RL, Haywood L, Lee DC, McKnight GS,
Griswold MD 1987 Transferrin messenger ribonucleic acid: molecular cloning and hormonal regulation in rat Sertoli Cells. Endocrinology 120:332
284. Ciechanover A, Schwartz AL, Dautry-Varsat A, Lodish HF 1983
Kinetics of internalization and recycling of transferrin and the
transferrin receptor in a human hepatoma cell line. J Biol Chem
258:9681
285. Octave J-N, Schneider Y-J, Trouet A, Crichton RR 1983 Iron
uptake and utilization by mammalian cells. I. Cellular uptake of
transferrin and iron. Trends Biochem Sci 8:217
286. Holmes SD, Bucci LR, Lipshultz LI, Smith RG 1983 Transferrin
binds specifically to pachytene spermatocytes. Endocrinology
113:1916
287. Sylvester SR, Griswold MD 1984 Localization of transferrin and
transferrin receptors in rat testes. Biol Reprod 31:195
288. Huggenvik J, Sylvester SR, Griswold MD 1985 Control Of transferrin mRNA synthesis in Sertoli cells. Ann NY Acad Sci 438:1
69
289. Morales C, Sylvester SR, Griswold MD 1987 Transport of iron
and transferrin synthesis by the seminiferous epithelium of the
rat in vivo. Biol Reprod 37:995
290. Wauben-Penris PJ, Strous GJ, van der Donk HA 1986 Transferrin receptors of isolated rat seminiferous tubules bind both rat
and human transferrin. Biol Reprod 35:1227
291. Wauben-Penris PJ, Veldscholte J, van der Ende A, van der Donk
HA 1988 The release of iron by Sertoli cells in culture. Biol
Reprod 38:1105
292. Roberts KP, Griswold MD 1990 Characterization of rat transferrin receptor cDNA: the regulation of transferrin receptor mRNA
in testes and in Sertoli cells in culture. Mol Endocrinol 4:531
293. Frieden E, Hsieh HS 1976 Ceruloplasmin: the copper transport
protein with essential oxidase activity. Adv Enzymol 44:187
294. Mareschal JC, Rama R, Crichton RR 1980 The role of ceruloplasmin in Fe(III)-transferrin formation in vitro. FEBS Lett
110:268
295. Beckman JK, Coniglio JG 1980 The metabolism of polyunsaturated fatty acids in rat Sertoli and germinal cells. Lipids 15:389
296. Marzouki AM, Coniglio JG 1982 Effect of essential fatty acid
deficiency on lipids of rat Sertoli and germinal cells. Biol Reprod
27:312
297. Fetterolf PM, Skinner MK 1987 Sertoli cells produce vitamin
binding proteins. Ann NY Acad Sci 513:480
298. Appling DR, Chytil F 1981 Evidence of a role for retinoic acid
(vitamin A-acid) in the maintenance of testosterone production
in male rats. Endocrinology 108:2120
299. Huggenvik J, Griswold MD 1981 Retinol binding protein in rat
testicular cells. J Reprod Fertil 61:403
300. Porter SB, Ong DE, Chytil F, Orgebin-Crist MC 1985 Localization
of cellular retinol-binding protein and cellular retinoic acid-binding protein in the rat testis and epididymis. J Androl 6:197
301. Galdieri M, Piantedosi R, Blaner WS 1989 Levels of binding
proteins for retinoids in cultured Sertoli cells: effect of medium
composition. Biochim Biophys Acta 1011:168
302. Blaner WS, Galdieri M, Goodman DS 1987 Distribution and levels
of cellular retinol- and cellular retinoic acid-binding protein in
various types of rat testis cells. Biol Reprod 36:130
303. Skinner MK, Griswold MD 1982 Secretion of testicular transferrin by cultured Sertoli cells is regulated by hormones and retinoids. Biol Reprod 27:211
304. Karl AF, Griswold MD 1980 Actions of insulin and vitamin A on
Sertoli cells. Biochem J 186:1001
305. Galdieri M, Monaco L 1983 Retinol increases synthesis and
secretion of Sertoli cell mannose-containing glycoproteins. Cell
Biol Int Rep 7:219
306. Galdieri M, Caporale C, Adamo S 1986 Calcium-, phospholipiddependent protein kinase activity of cultured rat Sertoli cells and
its modifications by vitamin A. Mol Cell Endocrinol 48:213
307. Galdieri M, Nistico L 1986 Vitamin A modifies the glycopeptide
composition of cultured Sertoli cells. J Androl 7:303
308. Unni E, Rao MRS 1986 Androgen binding protein levels and FSH
binding to testicular membranes in vitamin A deficient rats and
during subsequent replenishment with vitamin A. J Steroid
Biochem 25:579
309. Carson DD, Lennarz WJ 1983 Vitamin A deprivation selectively
lowers uridine nucleotide pools in cultured Sertoli cells. J Biol
Chem 258:1632
310. Chytil F 1988 Early effects of retinol and retinoic acid on protein
synthesis in retinol deficient rat testes. Biochem Biophys Res
Commun 151:53
311. Huang HF, Gould S, Boccabella AV 1989 Modification of Sertoli
cell functions in vitamin A-deficient rats. J Reprod Fertil 85:273
312. Haneji T, Maekawa M, Nishimune Y 1984 Vitamin A and folliclestimulating hormone synergistically induce differentiation of type
A spermatogonia in adult mouse cryptochid testis in vitro. Endocrinology 114:801
313. Bishop PD, Griswold MD 1987 Uptake and metabolism in retinol
in cultured Sertoli cells: Evidence for a kinetic model. Biochemistry 26:7511
314. Shingleton JL, Skinner MK, Ong DE 1989 Retinol esterification
70
315.
316.
317.
318.
319.
320.
321.
322.
323.
324.
325.
326.
327.
328.
329.
330.
331.
332.
333.
334.
335.
SKINNER
in Sertoli cells by lecithin-retinol acyltransferase. Biochemistry
28:9647
Shingleton JL, Skinner MK, Ong DE 1989 Characteristics of
retinol accumulation from serum retinol-binding protein by cultured Sertoli cells. Biochemistry 28:9641
Carson DD, Rosenberg LI, Blaner WS, Kato M, Lennarz WJ
1984 Synthesis and secretion of a novel binding protein from
retinol by a cell line derived from Sertoli cells. J Biol Chem
259:3117
Ong DE, Chytil F 1988 Presence of novel retinoic acid-binding
proteins in the lumen of rat epididymis. Arch Biochem Biophys
267:474
Jegou B, Laws AO, de Kretser DM 1984 Changes in testicular
function induced by short-term exposure of the rat testis to heat:
further evidence for interaction of germ cells, Sertoli cells and
Leydig cells. Int J Androl 7:244
Hatier R, Grignon G, Touati F 1982 Ultrastructural study of
seminiferous tubules in the rat after prenatal irradiation. Anat
Embryol 165:425
Pinon-Lataillade G, Velez de la Calle JF, Viguier-Martinez MC,
Gamier DH, Folliot R, Maas J, Jegou B 1988 Influence of germ
cells upon Sertoli cells during continuous low-dose rate gammairradiation of adult rats. Mol Cell Endocrinol 58:51
Pineau C, Velez de la Calle JF, Pinon-Lataillade G, Jegou B 1989
Assessment of testicular function after acute and chronic irradiation: further evidence for an influence of late spermatids on Sertoli
cell function in the adult rat. Endocrinology 124:2720
Bartlett JM, Kerr JB, Sharpe RM 1988 The selective removal of
pachytene spermatocytes usign methoxy acetic acid as an approach to the study in vivo of paracrine interactions in the testis.
J Androl 9:31
Francavilla S, Bellocci M, Martini M, Bruno B, Moscardelli S,
Fabbrini A, Properzi G 1982 Arrest of maturation in spermatogenesis. Boll Soc Ital Biol Sper 58:907
Morales CR, Alcivar AA, Hecht NB, Griswold MD 1989 Specific
mRNAs in Sertoli and germinal cells of testes from stage synchronized rats. Mol Endocrinol 3:725
Morris ID, Bardin CW, Musto NA, Thau RB, Gunsalus GL 1987
Evidence suggesting that germ cells influence the bidirectional
secretion of androgen binding protein by the seminiferous epithelium demonstrated by selective impairment of spermatogenesis
with busulphan. Int J Androl 10:691
Cheng CY, Grima J, Stahler MS, Lockshin RA, Bardin CW 1989
Testins are structurally related Sertoli cell proteins whose secretion is tightly coupled to the presence of germ cells. J Biol Chem
264:21386
Hansson V, Weddington SC, McLean WS, Smith AA, Nayfeh
SN, French FS, Ritzen EM 1975 Regulation of seminiferous
tubular function by FSH and androgen. J Reprod Fertil 44:363
Clausen OP, Purvis K, Hansson V 1979 Endocrine correlates of
meiosis in the male rat. Arch Androl 2:59
Rivarola MA, Sanchez P, Saez JM 1985 Stimulation of ribonucleic
acid and deoxyribonucleic acid synthesis in spermatogenic cells
by their coculture with Sertoli cells. Endocrinology 117:1796
van der Donk JA, de Ruiter-Bootsma AL, Ultee-van Gessel AM,
Wauben-Penris PJ 1986 Cell-cell interaction between rat Sertoli
cells and mouse germ cells in vitro. Exp Cell Res 164:191
Li LY, Seddon AP, Meister A, Risley MS 1989 Spermatogenic
cell-somatic cell interactions are required for maintenance of
spermatogenic cell glutathione. Biol Reprod 40:317
Vannelli BG, Barni T, Orlando C, Natali A, Serio M, Balboni GC
1988 Insulin-like growth factor-I (IGF-I) and IGF-I receptor in
human testis: an immunohistochemical study. Fertil Steril 49:666
Feig LA, Bellve' AR, Erickson NH, Klagsbrun MK 1980 Sertoli
cells contain a mitogenic polypeptide. Proc Natl Acad Sci USA
77:4774
Feig LA, Klagsbrun M, Bellve' AR 1983 Mitogenic polypeptide of
the mammalian seminiferous epithelium: biochemical characterization and partial purification. J Cell Biol 97:1435
Bellve' AR, Feig LA 1984 Cell proliferation in the mammalian
testis: biology of the seminiferous growth factor (SGF). Recent
Prog Horm Res 40:531
Vol. 12, No. 1
336. Buch JP, Lamb DJ, Lipshultz LI, Smith RG 1988 Partial characterization of a unique growth factor secreted by human Sertoli
cells. Fertil Steril 49:658
337. Suarez-Quian CA, Dai M, Onoda M, Kriss RM, Dym M 1989
Epidermal growth factor receptor localization in the rat and
monkey testes. Biol Reprod 41:921
338. Pollanen P, Soder O, Parvinen M 1989 Interleukin-1 alpha stimulation of spermatogonial proliferation in vivo. Reprod Fertil Dev
1:85
339. O'Brien DA, Gabel CA, Rockett DL, Eddy EM 1989 Receptormediated endocytosis and differential synthesis of mannose 6phosphate receptors in isolated spermatogenic and Sertoli cells.
Endocrinology 125:2973
340. Galdieri M, Zani BM, Monaco L, Ziparo E, Stefanini M 1983
Changes of Sertoli cell glycoproteins induced by removal of the
associated germ cells. Exp Cell Res 145:191
341. Galdieri M, Monaco L, Stefanini M 1984 Secretion of androgen
binding protein by Sertoli cells is influenced by contact with germ
cells. J Androl 5:409
342. Le Magueresse B, Le Gac F, Loir M, Jegou B 1986 Stimulation
of rat Sertoli cell secretory activity in vitro by germ cells and
residual bodies. J Reprod Fertil 77:489
343. Le Magueresse B, Jegou B 1988 In vitro effects of germ cells on
the secretory activity of Sertoli cells recovered from rats of different ages. Endocrinology 122:1672
344. Janecki A, Jakubowiak A, Steinberger A 1988 Effect of germ cells
on vectorial secretion of androgen binding protein and transferrin
by immature rat Sertoli cells in vitro. J Androl 9:126
345. Castellon E, Janecki A, Steinberger A 1989 Age-dependent Sertoli
cell responsiveness of germ cells in vivo. Int J Androl 12:439
346. Ireland ME, Welsh MJ 1987 Germ cell stimulation of Sertoli cell
protein phosphorylation. Endocrinology 120:1317
347. Schteingart HF, Rivarola MA, Cigorraga SB 1989 Hormonal and
paracrine regulation of gamma-glutamyl transpeptidase in rat
Sertoli cells. Mol Cell Endocrinol 67:73
348. Le Magueresse B, Jegou B 1986 Possible involvement of germ
cells in the regulation of oestradiol-17/3 and ABP secretion by
immature rat Sertoli cells (in vitro studies). Biochem Biophys Res
Commun 141:861
349. Le Magueresse B, Jegou B 1988 Paracrine control of immature
Sertoli cells by adult germ cells, in the rat (an in vitro study).
Cell-cell interactions within the testis. Mol Cell Endocrinol 58:65
350. Rivarola MA, Sanchez P, Saez JM 1986 Inhibition of RNA and
DNA synthesis in Sertoli cells by co-culture with spermatogenic
cells. Int J Androl 9:424
351. Le Magueresse B, Pineau C, Guillou F, Jegou B 1988 Influence of
germ cells upon transferrin secretion by rat Sertoli cells in vitro.
J Endocrinol 118:R13
352. Djakiew D, Dym M 1988 Pachytene spermatocyte proteins influence Sertoli cell function. Biol Reprod 39:1193
353. Stallard BJ, Griswold MD 1990 Germ cell regulation of Sertoli
cell transferrin mRNA levels. Mol Endocrinol 4:393
354. Persson H, Ayer-LeLievre C, Soder O, Villar MJ, Metsis M, Olson
L, Ritzen M, Hokfelt T 1990 Expression of beta-nerve growth
factor receptor mRNA in Sertoli cells downregulated by testosterone. Science 247:704
355. Ayer-LeLievre C, Olson L, Ebendal T, Hallbook F, Persson H
1988 Nerve growth factor mRNA and protein in the testis and
epididymis of mouse and rat. Proc Natl Acad Sci USA 85:2628
356. Olson L, Ayer-LeLievre C, Ebendal T, Seiger A1987 Nerve growth
factor-like immunoreactivities in rodent salivary glands and testis. Cell Tissue Res 248:275
357. Clermont Y 1958 Contractile elements in the limiting membranes
of the seminiferous tubules in the rat. Exp Cell Res 15:438
358. Lacy D, Rotblat J 1960 Study of normal and irradiated boundary
tissue of the seminiferous tubules of the rat. Exp Cell Res 21:49
359. Leeson CR, Leeson TS 1963 The postnatal development and
differentiation of the boundary tissue of the seminiferous tubule
of the rat. Anat Rec 147:243
360. Kagayama M, Irisawa S, Shirai M, Matsushita K 1965 Contractile
cells in the tissue surrounding the seminiferous tubules. Jpn
Excerpta Med 20:1124
February, 1991
CELL-CELL INTERACTIONS IN THE TESTIS
361. Crabo B 1963 Fine structure of the interstitial cells of the rabbit
testis. Z Zellforsch Mikrosk Anat 61:587
362. Ross MH, Long IR 1966 Contractile cells in human seminiferous
tubules. Science 153:1271
363. Ross MH 1967 The fine structure and development of the peritubular contractile cell component in the seminiferous tubules of
the mouse. Am J Anat 121:523
364. Fawcett DW, Heidger PM, Leak LV 1960 Lymph vascular system
of the interstitial tissue of the testis as revealed by electron
microscopy. J Reprod Fertil 19:109
365. McCord RG 1970 Fine structural observations of the peritubular
cell layer in the hamster testis. Protoplasma 69:283
366. Bressler RS, Ross MH 1972 Differentiation of peritubular myoid
cells of the testis: effects of intratesticular implantation of newborn mouse testes into normal and hypophysectomized adults.
Biol Reprod 6:148
367. Unsicker K, Burnstock G 1975 Myoid cells in the peritubular
tissue (Lamina propria) of the reptilian testis. Cell Tissue Res
163:545
368. Kormano M, Hovatta 0 1972 Contractility and histochemistry of
the myoid cell layer of the rat seminiferous tubule during postnatal
development. Z Anat Entwicklungsgesch 137:239
369. Suvanto 0, Kormano M 1970 The relation between in vitro
contractions of the rat seminiferous tubules and the cyclic stage
of the seminiferous epithelium. J Reprod Fertil 21:227
370. van Vorstenbosch CJ, Spek E, Colenbrander B, Wensing CJ 1984
Sertoli cell development of pig testis in the fetal and neonatal
period. Biol Reprod 31:565
371. Clermont Y, Perey B 1957 Quantitative study of the cell population of the seminiferous tubules in immature rats. Am J Anat
100:241
372. Flickinger CJ 1967 The postnatal development of the Sertoli cells
of the mouse. Z Zellforsch Mikrosk Anat 78:92
373. Hovatta O 1972 Effect of androgens and antiandrogens on the
development of the myoid cells of the rat seminiferous tubules
(organ culture). Z Zellforsch Mikrosk Anat 131:299
374. De Kretser DM, Kerr JB, Paulsen CA 1975 The peritubular tissue
in the normal and pathological human testis. An ultrastructural
study. Biol Reprod 12:317
375. Narbaitz R, Tolnai G, Jolly EE, Barwin N, McKay DE 1978
Ultrastructural studies on testicular biopsies from eighteen cases
of hypospermatogenesis. Fertil Steril 30:679
376. Millonig G, Morano E, Bollero E, Vecchietti G, Zanoio L 1978
Ultrastructural study of gonads in the complete and incomplete
feminization syndrome. Gynecol Obstet Invest 9:16
377. Gravis CJ 1978 Testicular involution after optic enucleation:
ultrastructure and alkaline phosphatase cytochemistry of the
peritubular tissue. Am J Anat 151:213
378. Kerr JB, Rich KA, de Kretser DM 1979 Effects of experimental
cryptorchidism on the ultrastructure and function of the Sertoli
cell and peritubular tissue of the rat testis. Biol Reprod 21:823
379. Lacy D, Rotblat J 1960 Study of normal and irradiated boundary
tissue of the seminiferous tubules of the rat. Exp Cell Res 21:49
380. Tung PS, Fritz IB 1978 Histopathological changes in testes of
adult inbred rats immunized against pachytene spermatocytes or
Sertoli cells. Int J Androl [Suppl] 2:459
381. Pollanen PP, Kallajoki M, Risteli L, Risteli J, Suominen JJ 1985
Laminin and type IV collagen in the human testis. Int J Androl
8:337
382. Hadley MA, Dym M 1987 Immunocytochemistry of extracellular
matrix in the lamina propria of the rat testis: electron microscopic
localization. Biol Reprod 37:1283
383. Tung PS, Fritz IB 1980 Interactions of Sertoli cells with myoid
cells in vitro. Biol Reprod 23:207
384. Cameron DF, Markwald RR 1981 Structural response of adult rat
Sertoli cells to peritubular fibroblasts in vitro. Am J Anat 160:343
385. Tung PS, Frit IB 1986 Extracellular matrix components and
testicular peritubular cells influence the rate and pattern of Sertoli
cell migration in vitro. Dev Biol 113:119
386. Tung PS, Fritz IB 1987 Morphogenetic restructuring and formation of basement membranes by Sertoli cells and testis peritubular
cells in co-culture: inhibition of the morphogenetic ca$cade by
387.
388.
389.
390.
391.
392.
393.
394.
395.
396.
397.
398.
399.
400.
401.
402.
403.
404.
405.
406.
407.
408.
409.
71
cyclic AMP derivatives and by blocking direct cell contact. Dev
Biol 120:139
Mather JP, Phillips DM 1984 Establishment of a peritubular
myoid-like cell line and interactions between established testicular cell lines in culture. J Ultrastruct Res 87:263
Tung PS, Fritz IB 1984 Extracellular matrix promotes rat Sertoli
cell histotype expression in vitro. Biol Reprod 30:213
Hadley MA, Byers SW, Suarez-Quian CA, Kleinman HK, Dym
M 1985 Extracellular matrix regulates Sertoli cell differentiation,
testicular cord formation, and germ cell development in vitro. J
Cell Biol 101:1511
Enders GC, Henson JH, Millette CF 1986 Sertoli cell binding to
isolated testicular basement membrane. J Cell Biol 103:1109
Mather JP, Wolpe SD, Gunsalus GL, Bardin CW, Phillips DM
1984 Effect of purified and cell-produced extracellular matrix
components on Sertoli cell function. Ann NY Acad Sci 438:572
Anthony CT, Skinner MK 1989 Actions of extracellular matrix
on Sertoli cell morphology and function. Biol Reprod 40:691
Tung PS, Fritz IB 1986 Cell-substratum and cell-cell interactions
promote testicular peritubular myoid cell histotypic expression in
vitro. Dev Biol 115:155
Byers SW, Hadley MA, Djakiew D, Dym M 1986 Growth and
characterization of polarized monolayers of epididymal epithelial
cells and Sertoli cells in dual environment culture chambers. J
Androl 7:59
Janecki A, Steinberger A 1986 Polarized Sertoli cell functions in
a new two-compartment culture system. J Androl 7:69
Hadley MA, Djakiew D, Byers SW, Dym M 1987 Polarized
secretion of androgen-binding protein and transferrin by Sertoli
cells grown in a bicameral culture system. Endocrinology 120:1097
Janecki A, Steinberger A 1987 Bipolar secretion of androgenbinding protein and transferrin by Sertoli cells cultured in a twocompartment culture chamber. Endocrinology 120:291
Janecki A, Steinberg A 1987 Vectorial secretion of transferrin and
androgen binding protein in Sertoli cell cultures: effect of extracellular matrix, peritubular myoid cells and medium composition.
Mol Cell Endocrinol 52:125
Janecki A, Steinberger A 1988 Experimental pitfalls in evaluating
vectorial protein secretion in vitro; Sertoli cell secretion of androgen-binding protein and transferrin in two-compartment culture
chambers. In Vitro Cell Dev Biol 24:518
Ailenberg M, Fritz IB 1989 Influences of follicle-stimulating hormone, proteases, and antiproteases on permeability of the barrier
generated by Sertoli cells in a two-chambered assembly. Endocrinology 124:1399
Ailenberg M, Tung PS, Pelletier M, Fritz IB 1988 Modulation of
Sertoli cell functions in the two-chamber assembly by peritubular
cells and by extracellular matrix. Endocrinology 122:2064
Ailenberg M, Fritz IB 1988 Control of levels of plasminogen
activator activity secreted by Sertoli cells maintained in a twochambered assembly. Endocrinology 122:2613
Hutson JC 1983 Metabolic cooperation between Sertoli cells and
peritubular cells in culture. Endocrinology 112:1375
Bols NC, Bowen BW, Byrne PA 1984 Rat Sertoli cells in culture
undergo metabolic co-operation with each other and with fibroblasts. J Reprod Fertil 70:191
Hutson JC, Stocco DM 1981 Peritubular cell influence on the
efficiency of androgen-binding protein secretion by Sertoli cells
in culture. Endocrinology 108:1362
Holmes SD, Lipshultz LI, Smith RG 1984 Regulation of transferrin secretion by human Sertoli cells cultured in the presence or
absence of human peritubular cells. J Clin Endocrinol Metab
59:1058
Cameron DF, Snydle E 1985 Selected enzyme histochemistry of
Sertoli cells. 2. Adult rat Sertoli cells in co-culture with peritubular fibroblasts. Andrologia 17:185
Ueda H, Tres LL, Kierszenbaum AL 1988 Culture patterns and
sorting of rat Sertoli cell secretory proteins. J Cell Sci 89:175
Skinner MK, Fritz IB 1986 Identification of a non-mitogenic
paracrine factor involved in mesenchymal-epithelial cell interactions between testicular peritubular cells and Sertoli cells. Mol
Cell Endocrinol 44:85
72
SKINNER
410. Hutson JC, Yee JB, Yee JA 1987 Peritubular cells influence
Sertoli cells at the level of translation. Mol Cell Endocrinol 52:11
411. Verhoeven G, Cailleau J 1988 Testicular peritubular cells secrete
a protein under androgen control that inhibits induction of aromatase activity in Sertoli cells. Endocrinology 123:2100
412. Morris PL, Vale WW, Cappel S, Bardin CW 1988 Inhibin production by primary Sertoli cell-enriched cultures: regulation by
follicle-stimulating hormone, androgens, and epidermal growth
factor. Endocrinology 122:717
413. Mallea LE, Machado AJ, Navaroli F, Rommerts FFG 1986 Epidermal growth factor stimulates lactate production and inhibits
cromatization in cultured Sertoli cells from immature rats. Int J
Androl 9:221
414. Nargolwalla C, McCabe D, Fritz IB 1990 Modulation of levels of
messenger RNA for tissue-type plasminogen activator in rat Sertoli cells, and levels of messenger RNA for plasminogen activator
inhibitor in testis peritubular cells. Mol Cell Endocrinol 70:73
415. Benahmed M, Esposito G, Sordoille TC, dePeretti E, Chauvin
MA, Ghiglieri C, Revol A, Morera AM 1989 Transforming growth
actor /3 and its related peptides in the testis: an intragonadal
polypeptide control system. Perspect Androl 53:191
416. Casella SJ, Smith EP, Van Wyk JJ, Joseph DR, Hynes MA, Hoyt
EC, Lund PK 1987 Isolation of rat testis cDNAs encoding an
insulin-like growth factor I precursor. DNA 6:325
417. Oonk RB, Grootegoed JA 1988 Insulin-like growth factor I (IGFI) receptors on Sertoli cells from immature rats and age-dependent
testicular binding of IGF-I and insulin. Mol Cell Endocrinol 55:33
418. Closset J, Gothot A, Sente B, Scippo ML, Igout A, Vandenbroeck
M, Dombrowicz D, Hennen G 1989 Pituitary hormones dependent
expression of insulin-like growth factors I and II in the immature
hypophysectomized rat testis. Mol Endocrinol 3:1125
419. Jost A, Magre S, Agelopoulos R 1981 Early stages of testicular
differentiation in the rat. Hum Genet 58:59
420. Leydig F 1850 Zur anatomie der mannlichen geschlechtsorganie
und analdrusen der saugetiere. Z Wiss Zool 2:1
421. Wattenberg LW 1958 Microscopic histochemical demonstration
of steroid-3/3-ol-dehydrogenase in tissue sections. J Histochem
Cytochem 6:225
422. Levy H, Deane HW, Rubin BL 1959 Visualization of steroid-3(8ol-dehydrogenase activity in tissues of intact and hypophysectomized rats. Endocrinology 65:932
423. Christensen AK, Mason NR 1965 Comparative ability of seminiferous tubules and interstitial tissue of rat testes to synthesize
androgens from progesterone-4-14C in vitro. Endocrinology 76:646
424. Hall PF, Irby DL, de Kretser DM 1969 Conversion of cholesterol
to androgens by rat testes: comparison of interstitial cells and
seminiferous tubules. Endocrinology 84:488
425. Bell JB 1972 Interconversion of testosterone and androstenedione
in the human testis: a comparison between the activities displayed
by the interstitium and the seminiferous tubules. Experientia
28:212
426. Cooke BA, de Jong FH, van der Molen NH, Rommerts FG 1972
Endogenous testosterone concentrations in rat testis interstitial
tissue and seminiferous tubules during in vitro incubation. Nature
237:255
427. Lostroh AJ 1969 Regulation by FSH and ILSH (LH) at reproductive function in the immature male rat. Endocrinology 85:438
428. Cooke BA, Van Beurden WMO, Rommerts FFG, van der Molen
NJ 1972 Effects of trophic hormones on 3',5'-cyclic AMP levels
in rat testis interstitial tissue and seminiferous tubules. FEBS
Lett 25:83
429. Moyle WR, Ramachandran J 1973 Effect of LH on steroidogenesis
and cyclic AMP accumulation in rat Leydig cell preparations and
mouse tumor Leydig cells. Endocrinology 93:127
430. Dorrington JH, Fritz IB 1974 Effects of gonadotropins on cyclic
AMP production by isolated seminiferous tubule and interstitial
cell preparations. Endocrinology 94:395
431. Steinberger A 1975 Studies on spermatogenesis and steroidogenesis in culture. Am Zool 15:273
432. Clermont Y, Harvey SC 1965 Duration of the cycle of the seminiferous epithelium of normal, hypophysectomized and hypophysectomized-hormone treated albino rats. Endocrinology 76:80
Vol. 12, No. 1
433. Cunningham GR, Huckins C 1979 Persistence of complete spermatogenesis in the presence of low intratesticular concentrations
of testosterone. Endocrinology 105:177
434. Huang HF, Nieschlag E 1986 Suppression of the intratesticular
testosterone is associated with quantitative changes in spermatogonial populations in intact adult rats. Endocrinology 118:619
435. Friend DS, Gilula NB 1972 Variations in tight and gap junctions
in mammalian tissues. J Cell Biol 53:758
436. Nagano T, Suzuki F 1976 Freeze-fracture observations on the
intercellular junctions of Sertoli cells and of Leydig cells in the
human testis. Cell Tissue Res 166:37
437. Connell CJ, Christensen AK 1975 The ultrastructure of the canine
testicular interstitial tissue. Biol Reprod 12:368
438. Christensen AK 1975 Leydig cells. In: Hamilton DW, Greep RO
(eds) Handbook of Physiology, sect 7, vol 5. American Physiological Society, Washington DC, p 57
439. Connell CJ, Connell GM 1977 The interstitial tissue of the testis.
In: Johnson A, Gomes W (eds) The Testis. Academic Press New
York, vol 4:333
440. Adashi EY, Hsueh AJW 1981 Autoregulation of androgen production in a primary culture of rat testicular cells. Nature 293:737
441. Darney Jr KJ, Ewing L 1981 Autoregulation of testosterone
secretion in perfused rat testes. Endocrinology 109:993
442. Dufau ML 1988 Endocrine regulation and communicating functions of the Leydig cell. Annu Rev Physiol 50:483
443. Hedger MP, Eddy EM 1987 The heterogeneity of isolated adult
rat Leydig cells separated on Percoll density gradients: an immunological, cytochemical and functional analysis. Endocrinology
121:1824
444. Hedger MP, Eddy EM 1990 Leydig cell cooperation in vitro:
evidence for communication between adult rat Leydig cells. J
Androl 11:9
445. Sanborn BM, Steinberger A, Meistrich ML, Steinberger E 1975
Androgen binding sites in testis cell fractions as measured by a
nuclear exchange assay. J Steroid Biochem 6:1459
446. Sanborn BM, Steinberger A, Tcholakian RK, Steinberger E 1977
Direct measurement of androgen receptors in cultured Sertoli
cells. Steroids 29:493
447. Sanborn BM, Steinberger A, Tcholakian RK 1979 Effects of ionic
strength on the interaction of androgens with Sertoli cell nuclei.
Steroids 34:401
448. Mulder E, Peters MJ, De Vries J, Van Der Molen HJ 1975
Characterization of a nuclear receptor for testosterone in seminiferous tubules of mature rat testes. Mol Cell Endocrinol 2:171
449. Schmidt WN, Danzo BJ 1980 Androgen and progesterone binding
components in cytosol prepared from cultures enriched in Sertoli
cells from immature rat testes. Biol Reprod 23:495
450. Tindall DJ, Miller DA, Means AR 1977 Characterization of androgen receptor in Sertoli cell-enriched testis. Endocrinology
101:13
451. Tsai YH, Sanborn BM, Steinberger A, Steinberger E 1980 Sertoli
cell chromatin acceptor sites for androgen-receptor complexes. J
Steroid Biochem 13:711
452. Verhoeven G, Cailleau I 1988 Follicle-stimulating hormone and
androgens increase the concentrations of the androgen receptor
in Sertoli cells. Endocrinology 122:1541
453. Buzek SW, Sanborn BM 1988 Increase in testicular androgen
receptor during sexual maturation in the rat. Biol Reprod 39:39
454. Sanborn BM, Wagle JR, Steinberger A 1984 Control of androgen
cytosol receptor concentrations in Sertoli cells: effect of androgens. Endocrinology 114:2388
455. Buzek SW, Caston LA, Sanborn BM 1987 Evidence for agedependent changes in Sertoli cell androgen receptor concentration. J Androl 8:83
456. Nakhla AM, Mather JP, Janne OA, Bardin CW 1984 Estrogen
and androgen receptors in Sertoli, Leydig, myoid, and epithelial
cells: effects of time in culture and cell density. Endocrinology
115:121
457. Isomaa V, Parvinen M, Janne OA, Bardin CW 1985 Nuclear
androgen receptors in different stages of the seminiferous epithelial cycle and the interstitial tissue of rat testis. Endocrinology
116:132
February, 1991
CELL-CELL INTERACTIONS IN THE TESTIS
458. Louis BG, Fritz IB 1979 Follicle stimulating hormone and testosterone independently increase the production of androgen binding
protein by Sertoli cells in culture. Endocrinology 104:454
459. Cailleau J, Heyns W, Verhoeven G 1984 A filter disc assay for the
measurement and characterization of androgen-binding protein
in unconcentrated media from Sertoli cell-enriched cultures. J
Steroid Biochem 21:691
460. Rommerts FFG, Kruger-Sewnarain BCh, Van Woerkom-Blik A,
Grootegoed JA, Van Der Molen HJ 1978 Secretion of proteins by
Sertoli cell enriched cultures: effects of FSH, dibutyryl cyclic
AMP and testosterone and correlation with secretion of oestradiol
and ABP. Mol Cell Endocrinol 10:39
461. Roberts K, Griswold MD 1989 Testosterone induction of cellular
proteins in cultured Sertoli cells from hypophysectomized rats
and rats of different agents. Endocrinology 125:1174
462. Ailenberg M, McCabe D, Fritz IB 1990 Androgens inhibit plasminogen activator activity secreted by Sertoli cells in culture in a
two-chambered assembly. Endocrinology 126:1561
463. Skinner MK, Fritz IB 1985 Androgen stimulation of Sertoli cell
function is enhanced by peritubular cells. Mol Cell Endocrinol
40:115
464. Parmentier M, Inagami T, Pochet R, Desclin JC 1983 Pituitarydependent renin-like immunoreactivity in the rat testis. Endocrinology 112:1318
465. Pandey KN, Maki M, Inagami T 1984 Detection of renin mRNA
in mouse testis by hybridization with renin cDNA probe. Biochem
Biophys Res Commun 125:662
466. Pandey KN, Ascoli M, Inagami T 1985 Induction of renin activity
by gonadotropic hormones in cultured Leydig tumor cells. Endocrinology 117:2120
467. Pandey KN, Inagami T 1986 Regulation of renin angiotensins by
gonadotropic hormones in cultured murine Leydig tumor cells.
Release of angiotensin but not renin. J Biol Chem 261:3934
468. Douglass J, Cox B, Quinn B, Civelli O, Herbert E 1987 Expression
of the Prodynorphin gene in male and female mammalian reproductive tissues. Endocrinology 120:707
469. Nicholson HD, Swann RW, Burford GD, Wathes DC, Porter DG,
Pickering BT 1983 Identification of oxytoxin and vasopressin in
the testis and in adrenal tissue. Regul Pept 8:141
470. Guldenaar SEF, Pickering BT 1985 Immunocytochemical evidence for the presence of oxytocin in rat testis. Cell Tissue Res
240:485
471. Pickering BT, Ayad VJ, Birkett SD, Gilbert CL, Guldenaar SEF,
Nicholson HD, Worley RTS, Wathes DC 1990 Neurohypophysial
peptides in the gonads: are they real and do they have a function?
Reprod Fertil Dev 2:245
472. Chen CL, Madigan MB 1987 Regulation of testicular proopiomelanocortin gene expression. Endocrinology 121:590
473. Gizang-Ginsberg E, Wolgemuth DJ 1987 Expression of the proopiomelanocortin gene is developmentally regulated and affected
by germ cells in the male mouse reproductive system. Proc Natl
Acad Sci USA 84:1600
474. Bardin CW, Chen CL, Morris PL, Gerendai I, Boitani C, Liotta
AS, Margioris A, Krieger DT 1987 Proopiomelanocortic-derived
peptides in testis, ovary, and tissues of reproduction. Recent Prog
Horm Res 43:1
475. Valenca MM, Negro-Vilar A 1986 Proopiomelanocortin-derived
peptides in testicular interstitial fluid: characterization and
changes in secretion after human chorionic gonadotropin or luteinizing hormone-releasing hormone analog treatment. Endocrinology 118:32
476. Fabbri A, Knox G, Buczko E, Dufau ML 1988 Beta-endorphin
production by the fetal Leydig cell: regulation and implications
for paracrine control of Sertoli cell function. Endocrinology
122:749
477. Fabbri A, Dufau ML 1988 Hormonal regulation of beta-endorphin
in the testis. J Steroid Biochem 30:347
478. Lebouille JL, Burbach JP, De Kloet ER, Rommerts FF 1986 TEndorphin-generatingendopeptidase: distribution in body tissues
and cellular localization in rat testis. Endocrinology 118:372
479. Fabbri A, Tsai-Morris CH, Luna S, Fraioli F, Dufau ML 1985
480.
481.
482.
483.
484.
485.
486.
487.
488.
489.
490.
491.
492.
493.
494.
495.
496.
497.
498.
499.
500.
501.
73
Opiate receptors are present in the rat testis. Identification and
localization in Sertoli cells. Endocrinology 117:2544
Bardin CW, Morris PL, Chen CL, Boitani C, Krieger DT 1987
The action of pro-opiomelanocortin-derived peptides on testicular
cells. Ann NY Acad Sci 512:308
Gerendai I, Shaha C, Gunsalus GL, Bardin CW 1986 The effects
of opioid receptor antagonists suggest that testicular opiates regulate Sertoli and Leydig cell function in the neonatal rat. Endocrinology 118:2039
Morris PL, Vale WW, Bardin CW 1987 Beta-endorphin regulation of FSH-stimulated inhibin production is a component of a
short loop system in testis. Biochem Biophys Res Commun
148:1513
Boitani C, Farini D, Canipari R, Bardin CW 1989 Estradiol and
plasminogen activator secretion by cultured rat Sertoli cells in
response to melanocyte-stimulating hormones. J Androl 10:202
Orth JM 1986 FSH-induced Sertoli cell proliferation in the developing rat is modified by /3-endorphin produced in the testis.
Endocrinology 119:1876
Orth JM, Boehm R 1990 Endorphin suppresses FSH-stimulated
proliferation is isolated neonatal Sertoli cells by a pertussis toxinsensitive mechanism. Anat Rec 226:320
Juniewicz PE, Keeney DS, Ewing LL 1988 Effect of adrenocorticotropin and other proopiomelanocortin-derived peptides on testosterone secretion by the in vitro perfused testis. Endocrinology
122:891
Margioris AN, Koukoulis G, Grino M, Chrousos GP 1989 In vitroperifused rat testes secrete (8-endorphin and dynorphin: their
effect on testosterone secretion. Biol Reprod 40:776
Rich KA, de Kretser DM 1977 Effect of differing degrees of
destruction of the rat seminiferous epithelium on levels of serum
follicle stimulating hormone and androgen binding protein. Endocrinology 101:959
Aoki A, Fawcell DW 1978 Is there a local feedback from the
seminiferous tubules affecting activity of the Leydig cells? Biol
Reprod 19:144
Rich KA, Kerr JB, de Kretser DM 1979 Evidence for Leydig cell
dysfunction in rats with seminiferous tubule damage. Mol Cell
Endocrinol 13:123
Surina MN 1980 Dynamics of development of the interstitial
tissue and seminiferous tubules in the testis of human fetuses.
Probl Endokrinol 26:41
Kula K, Romer TE, Wlodarczyk WP 1980 Somatic and germinal
cells' interrelationship in the course of seminiferous tubule maturation in man. Arch Androl 4:9
Steinberger E, Root A, Ficher M, Smith KD 1973 The role of
androgens in the initiation of spermatogenesis in man. J Clin
Endocrinol Metab 37:746
Neaves WB, Johnson L, Petty CS 1987 Seminiferous tubules and
daily sperm production in older adult men with varied numbers
of Leydig cells. Biol Reprod 36:301
Kerr JB, Rich KA, de Kretser DM 1979 Alterations of the fine
structure and androgen secretion of the interstitial cells in the
experimentally cryptorchid rat testis. Biol Reprod 20:409
de Kretser DM, Sharpe RM, Swanston IA 1979 Alterations in
steroidogenesis and human chorionic gonadotropin binding in the
cryptorchid rat testis. Endocrinology 105:135
Risbridger GP, Kerr JB, Peake R, Rich KA, de Kretser DM 1981
Temporal changes in rat Leydig cell function after the induction
of bilateral cryptorchidism. J Reprod Fertil 63:415
Risbridger GP, Kerr JB, de Kretser DM 1981 Evaluation of Leydig
cell function and gonadotropin binding in unilateral and bilateral
cryptochidism: evidence for local control of Leydig cell function
by the seminiferous tubule. Biol Reprod 24:534
Risbridger GP, Kerr JB, Peake RA, de Kretser DM 1981 An
assessment of Leydig cell function after bilateral or unilateral
efferent duct ligation: further evidence for local control of Leydig
cell function. Endocrinology 109:1234
Bergh A, Damber JE 1984 Local regulation of Leydig cells by the
seminiferous tubules. Effect of short-term cryptorchidism. Int J
Androl 7:409
Jegou B, Laws AO, de Kretser DM 1983 The effect ofcryptorchi-
74
502.
503.
504.
505.
506.
507.
508.
509.
510.
511.
512.
513.
514.
515.
516.
517.
518.
519.
520.
521.
522.
523.
524.
SKINNER
dism and subsequent orchidopexy on testicular function in adult
rats. J Reprod Fertil 69:137
Jegou B, Peake RA, Irby DC, de Kretser DM 1984 Effects of the
induction of experimental cryptorchidism and subsequent orchidopexy on testicular function in immature rats. Biol Reprod
30:179
Bergh A 1982 Local differences in Leydig cell morphology in the
adult rat testis: evidence for a local control of Leydig cells by
adjacent seminiferous tubules. Int J Androl 5:325
Bergh A 1983 Paracrine regulation of Leydig cells by the seminiferous tubules. Int J Androl 6:57
Bergh A 1985 Development of stage-specific paracrine regulation
of Leydig cells by the seminiferous tubules. Int J Androl 8:80
Reventos J, Benahmed M, Tabone E, Saez JM 1983 Modulation
of Leydig cell activity by Sertoli cell: an in vitro sutdy. C R Acad
Sci [III] 296:123
Tabone E, Benahmed M, Reventos, J, Saez JM 1984 Interactions
between immature porcine Leydig and Sertoli cells in vitro. An
ultrastructural and biochemical study. Cell Tissue Res 237:357
Benahmed M, Reventos J, Tabone E, Saez JM 1985 Cultured
Sertoli cell-mediated FSH stimulatory effect on Leydig cell steroidogenesis. Am J Physiol 248:E176
Perrard-Sapori MH, Chatelain P, Vallier P, Saez JM 1986 In
vitro interactions between Sertoli cells and steroidogenic cells.
Biochem Biophys Res Commun 134:957
Saez JM, Tabone E, Perrard-Sapori MH, Rivarola MA 1986
Paracrine role of Sertoli cells. Med Biol 63:225
Saez JM, Sanchez P, Berthelon MC, Avallet O 1989 Regulation
of pig Leydig cell aromatase activity by gonadotropins and Sertoli
cells. Biol Reprod 41:813
Reventos J, Perrard-Sapori MH, Chatelain PG, Saez JM 1989
Leydig cell and extracellular matrix effects on Sertoli cell function: biochemical and morphologic studies. J Androl 10:359
Parvinen M, Nikula H, Huhtaniemi I 1984 Influence of rat
seminiferous tubules on Leydig cell testosterone production in
vitro. Mol Cell Endocrinol 37:331
Bartlett JM, Wu FC, Sharpe RM 1987 Enhancement of Leydig
cell testosterone secretion by isolated seminiferous tubules during
co-perifusion in vitro: comparison with static co-culture systems.
Int J Androl 10:603
Benahmed M, Grenot C, Tabone E, Sanchez P, Morera AM 1985
FSH regulates cultured Leydig cell function via Sertoli cell proteins: an in vitro study. Biochem Biophys Res Commun 132:729
Janecki A, Jakubowiak A, Lukaszyk A 1985 Stimulatory effect of
Sertoli cell secretory products on testosterone secretion by purified Leydig cells in primary culture. Mol Cell Endocrinol 42:235
Verhoeven G, Cailleau J 1985 A factor in spent media from Sertoli
cell-enriched cultures that stimulates steroidogenesis in Leydig
cells. Mol Cell Endocrinol 40:57
Papadopoulos V, Carreau S, Drosdowsky MA 1986 Effects of
seminiferous tubule secreted factor(s) on Leydig cell cyclic AMP
production in mature rat. FEBS Lett 202:74
Benahmed M, Tabone E, Grenot C, Sanchez P, Chauvin MA,
Morera AM 1986 Paracrine control of Leydig cell activity by FSH
dependent proteins from Sertoli cells: an in vitro study. J Steroid
Biochem 24:311
Verhoeven G, Cailleau J 1986 Specificity and partial purification
of a factor in spent media from Sertoli cell-enriched cultures that
stimulates steroidogenesis in Leydig cells. J Steroid Biochem
25:393
Papadopoulos V, Kamtchouing P, Drosdowsky MA, Hochereau
de Reviers MT, Carreau S 1987 Adult rat Sertoli cells secrete a
factor or factors which modulate Leydig cell function. J Endocrinol 114:459
Verhoeven G, Cailleau J 1987 A Leydig cell stimulatory factor
produced by human testicular tubules. Mol Cell Endocrinol 49:137
Perrard-Sapori MH, Chatelain PC, Rogemond N, Saez JM 1987
Modulation of Leydig cell functions by culture with Sertoli cells
or with Sertoli cell-conditioned medium: effect of insulin, somatomedin-C and FSH. Mol Cell Endocrinol 50:193
Liu YX, Dahl KD 1988 A factor(s) produced by Sertoli cells
525.
526.
527.
528.
529.
530.
531.
532.
533.
534.
535.
536.
537.
538.
539.
540.
541.
542.
543.
544.
545.
Vol. 12, No. 1
stimulates androgen biosynthesis by Leydig cells in neonatal rats.
Sci Sin [B] 31:818
Carreau S, Papadopoulos V, Drosdowsky MA 1988 Paracrine
regulation of Leydig cell aromatase in the rat: development with
age. Pathol Biol 36:1002
Carreau S, Papadopoulos V, Drosdowsky MA 1988 Stimulation
of adult rat Leydig cell aromatase activity by a Sertoli cell factor.
Endocrinology 122:1103
Saez JM, Sanchez P, Berthelon MC, Avallet O 1989 Regulation
of pig Leydig cell aromatase activity by gonadotropins and Sertoli
cells. Biol Reprod 41:813
Syed V, Khan SA, Ritzen EM 1985 Stage-specific inhibition of
interstitial cell testosterone secretion by rat seminiferous tubules
in vitro. Mol Cell Endocrinol 40:257
Benahmed M, Morera AM, Chauvin MA 1986 Evidence for a
Sertoli cell, FSH-suppressible inhibiting factor(s) of testicular
steroidogenic activity. Biochem Biophys Res Commun 139:169
Syed V, Khan SA, Lindh M, Ritzen EM 1987 Ontogeny and
cellular origin of a rat seminiferous tubule factor(s) that inhibits
LH-dependent testosterone production by interstitial cells in vitro. Int J Androl 10:711
Papadopoulos V, Kamtchouing P, Drosdowsky MA, Carreau S
1987 Spent media from immature seminiferous tubules and Sertoli
cells inhibit adult rat Leydig cell aromatase activity. Horm Metab
Res 19:62
Syed V, Khan SA, Lindh M, Ritzen EM 1988 Mechanism of
action of the factor(s) secreted by rat seminiferous tubules and
inhibiting interstitial cell testosterone production in vitro. Acta
Endocrinol (Copenh) 119:427
Takase M, Tsutsui K, Kawashima S 1988 Inhibitory effect of
Sertoli cell-cultured media on LH binding to mouse Leydig cells
in culture. Endocrinol Jpn 35:285
Syed V, Lindh M, Khan SA, Ritzen EM 1989 Hormonal regulation
of a rat seminiferous tubule factor which inhibits LH action on
interstitial cells. Int J Androl 12:464
Vihko KK, Huhtaniemi 11989 A rat seminiferous epithelial factor
that inhibits Leydig cell cAMP and testosterone production:
mechanism of action, stage-specific secretion, and partial characterization. Mol Cell Endocrinol 65:119
Syed V, Karpe B, Ploen L, Ritzen EM 1986 Regulation of interstitial cell function by seminiferous tubules in intact and cryptorchid rats. Int J Androl 9:271
Sharpe RM, Cooper 11984 Intratesticular secretion of a factor(s)
with major stimulatory effects on Leydig cell testosterone secretion in vitro. Mol Cell Endocrinol 37:159
Sharpe RM 1985 Intratesticular regulation of testosterone secretion: comparison of the effects and interactions of hCG, an LHRH
agonist and testicular interstitial fluid on Leydig cell testosterone
secretion in vitro. Mol Cell Endocrinol 41:247
Risbridger GP, Jenkin G, de Kretser DM 1986 The interaction of
hCG, hydroxysteroids and interstitial fluid on rat Leydig cell
steroidogenesis in vitro. J Reprod Fertil 77:239
Sharpe RM, Kerr JB, Fraser HM, Bartlett JM 1986 Intratesticular factors and testosterone secretion. Effect of treatments that
alter the level of testosterone within the testis. J Androl 7:180
Sharpe RM, Kerr JB, Cooper I, Bartlett JM 1986 Intratesticular
factors and testosterone secretion: the effect of treatment with
ethane dimethanesulphonate (EDS) and the induction of seminiferous tubule damage. Int J Androl 9:285
Bartlett JM, Sharpe RM 1987 Effect of local heating of the rat
testis on the levels of interstitial fluid of a putative paracrine
regulator of the Leydig cells and its relationship to changes in
Sertoli cell secretory function. J Reprod Fertil 80:279
Bartlett JMS, Sharpe RM 1987 Effect of local heating of the rat
testis on the levels in interstitial fluid of a putative paracrine
regulator of the Leydig cells and its relationship to changes in
Sertoli cell secretory function. J Reprod Fertil 80:279
Sharpe RM, Cooper 11987 Relationship between the exposure of
Leydig cells to factor(s) present in testicular interstitial fluid and
changes in their capacity to secrete testosterone during culture or
after hCG-induced desensitization. Mol Cell Endocrinol 51:105
Ishida H, Risbridger GP, de Kretser DM 1987 Variation in the
L
February, 1991
546.
547.
548.
549.
550.
551.
552.
553.
554.
555.
556.
557.
558.
559.
560.
561.
562.
563.
564.
565.
566.
567.
V
CELL-CELL INTERACTIONS IN THE TESTIS
effect of a nongonadotropic Leydig cell stimulating factor in
testicular interstitial fluid after exposure of the testis to a single
episode of heat treatment. J Androl 8:247
Maddocks S, Sharpe RM 1989 Interstitial fluid volume in the rat
testis: androgen-dependent regulation by the seminiferous tubules? J Endocrinol 120:215
Dorrington JH, Armstrong DT 1975 Follicle-stimulating hormone
stimulates estradiol-17/3 synthesis in cultured Sertoli cells. Proc
Natl Acad Sci USA 72:2677
Brinkmann AO, Mulder E, Lamers-Stahlhofen GJM, Mechielsen
MJ, Van der Molen HJ 1972 An oestradiol receptor in rat testis
interstitial tissue. FEBS Lett 26:301
Rommerts FF, Brinkman AO 1981 Modulation of steroidogenic
activities in testis Leydig cells. Mol Cell Endocrinol 21:15
Valladares LE, Payne AH 1979 Induction of testicular aromatization by luteinizing hormone in mature rats. Endocrinology
105:431
Sharpe RM, Fraser HM 1980 Leydig cell receptors for luteinizing
hormone releasing hormone and its agonists and their modulation
of administration or deprivation of the releasing hormone.
Biochem Biophys Res Commun 95:256
Sharpe RM, Fraser HM, Cooper I, Rommerts FF 1981 SertoliLeydig cell communication via an LHRH-like factor. Nature
290:785
Sharpe RM Fraser HM, Cooper I, Rommerts FF 1982 The secretion, measurement, and function of a testicular LHRH-like factor.
Ann NY Acad Sci 383:272
Sharpe RM 1984 Intratesticular factors controlling testicular
function. Biol Reprod 30:29
Kerr JB, Sharpe RM 1985 Follicle-stimulating hormone induction
of Leydig cell maturation. Endocrinology 116:2592
Sharpe RM, Cooper 11987 Comparison of the effects on purified
Leydig cells of four hormones (oxytocin, vasopressin, opiates and
LHRH) with suggested paracrine roles in the testis. J Endocrinol
113:89
Saint Pol PS, Hermand E, Tramu G 1988 Paracrine factors in
adult rat testis gonadotropin control of opioids and LHRH-like
peptide. Andrologia 20:173
Bourne GA, Regiani S, Payne AH, Marshall JC 1980 Testicular
GnRH receptors-characterization and localization on interstitial
tissue. J Clin Endocrinol Metab 51:407
Clayton RN, Katikineni M, Chan V, Dufau ML, Catt KJ 1980
Direct inhibition of testicular function by gonadotropin-releasing
hormone: mediation by specific gonadotropin-releasing hormone
receptors in interstitial cells. Proc Natl Acad Sci USA 77:4459
Lefebvre FA, Reeves JJ, Seguin C, Massicotte J, Labrie F 1980
Specific binding of a potent LHRH agonist in rat testis. Mol Cell
Endocrinol 20:127
Hedger MP, Risbridger GP, de Kretser DM 1985 Autoradiographical localization of luteinizing hormone releasing hormone
(LHRH) receptors on rat testicular intertubular cells fractionated
on Percoll density gradients. Aust J Biol Sci 38:435
Sharpe RM, Doogan DG, Cooper 11983 Direct effects of a luteinizing hormone-releasing hormone agonist on intratesticular levels
of testosterone and interstitial fluid formation in intact male rats.
Endorinology 113:1306
Sharpe RM, Doogan DG, Cooper I 1983 Factors determining
whether the direct effects of an LHRH agonist on Leydig cell
function in vivo are stimulatory or inhibitory. Mol Cell Endocrinol
32:57
Hedger MP, Robertson DM, Tepe SJ, Browne CA, de Kretser
DM 1986 Degradation of luteinizing hormone-releasing hormone
(LHRH) and an LHRH agonist by the rat testis. Mol Cell Endocrinol 46:59
Dutlow CM, Millar RP 1981 Rat testis immunoreactive LH-RH
differs structurally from hypothalamic LH-RH. Biochem Biophys
Res Commun 101:486
Bhasin S, Heber D, Peterson M, Swerdloff R1983 Partial isolation
and characterization of testicular GnRH-like factors. Endocrinology 112:1144
Arimura A, Turkelson CM 1984 LHRH-like substance in the rat
testis. Ann NY Acad Sci 438:390
75
568. Tres LL, Smith EP, Svoboda ME, Van Wyk JJ, Kierzenbaum AL
1986 Immunoreactive sites and accumulation of somatomedin-C
in rat Sertoli-spermatogenic cell co-cultures. Exp Cell Res 162:33
569. Chatelain PG, Naville D, Saez JM 1987 Somatomedin-C/insulinlike growth factor 1-like material secreted by porcine Sertoli cells
in vivo: characterization and regulation. Biochem Biophys Res
Commun 146:1009
570. Benahmed M, Morera AM, Chauvin MC, de Peretti E 1987
Somatomedin C/insulin-like growth factor-1 as a possible intratesticular regulator of Leydig cell activity. Mol Cell Endocrinol
50:69
571. Handelsman DJ, Spaliviero JA, Scott CD, Baxter RC 1985 Identification of insulin-growth factor-I and its receptors in the rat
testis. Acta Endocrinol (Copenh) 109:543
572. Lin T, Blaisdell J, Haskell JF 1987 Type I IGF receptors of Leydig
cells are upregulated by human chorionic gonadotropin. Biochem
Biophys Res Commun 149:852
573. Kasson BG, Hsueh AJ 1987 Insulin-like growth factor-I augments
gonadotropin-stimulated androgen biosynthesis by cultured rat
testicular cells. Mol Cell Endocrinol 52:27
574. Morera AM, Chauvin MA, de Peretti E, Binoux M, Benahmed M
1987 Somatomedin C/insulin-like growth factor 1: an intratesticular differentiative factor of Leydig cells? Horm Res 28:50
575. Haugen TB, Fritzson P, Hansson V 1987 Cellular localization and
developmental changes of deoxyribonucleoside-activated nucleotidase in the rat testis. Int J Biochem 19:193
576. Lin T, Haskell J, Vinson N, Terracio L 1986 Direct stimulatory
effects of insulin-like growth factor-I on Leydig cell steroidogenesis in primary culture. Biochem Biophys Res Commun 137:950
577. Verhoeven G, Cailleau J 1989 Tubule-Leydig cell interactions.
Andrology 53:227
578. Ascoli M 1981 Regulation of gonadotropin receptors and gonadotropin responses in a clonal strain of Leydig tumor cells by
epidermal growth factor. J Biol Chem 256:179
579. Welsh Jr TH, Hsueh AJW 1982 Mechanism of the inhibitory
action of epidermal growth factor on testicular androgen biosynthesis in vitro. Endocrinology 110:1498
580. Verhoeven G, Cailleau J 1986 Stimulatory effects of epidermal
growth factor on steroidogenesis in Leydig cells. Mol Cell Endocrinol 47:99
581. Pignataro OP, Ascoli M 1990 Studies with insulin and insulinlike growth factor-1 show that the increased labeling of phosphatidylinositol-3,4-bisphosphate is not sufficient to elicit the diverse
actions of epidermal growth factor on MA-10 Leydig tumor cells.
Mol Endocrinol 4:758
582. Teerds KJ, Rommerts FF, Dorrington JH 1990 Immunohistochemical detection of transforming growth factor-alpha in Leydig
cells during the development of rat testis. Mol Cell Endocrinol
69:R1
583. Avallet O, Vigier M, Perrard-Sapori MH, Saez JM 1987 Transforming growth factor /? inhibits Leydig cell functions. Biochem
Biophys Res Commun 146:575
584. Lin T, Blaisdell J, Haskell JF 1987 Transforming growth factor0 inhibits Leydig cell steroidogenesis in primary culture. Biochem
Biophys Res Commun 146:387
585. Morera AM, Cochet C, Keramidas M, Chauvin MA, de Peretti E,
Benahmed M 1988 Direct regulating effects of transforming
growth factor /3 on the Leydig cell steroidogenesis in primary
culture. J Steroid Biochem 30:443
586. Fauser BC, Hsueh AJ 1988 Effect of transforming growth factor0 on human chorionic gonadotropin induced testosterone production by cultured rat testicular cells. Life Sci 43:1363
587. Benahmed M, Cochet C, Keramidas M, Chauvin MA, Morera AM
1988 Evidence for a FSH dependent secretion of a receptor
reactive transforming growth factor /3-like material by immature
Sertoli cells in primary culture. Biochem Biophys Res Commun
154:1222
588. McCullagh DR 1932 Dual endocrine activity of the testis. Science
76:19
589. Franchimont P, Verstraelen-Proyard J, Hazee-Hagelstein MT,
Renard CH, Demoulin A, Bourguignon JP, Hustin J 1979 Inhibin:
from concepts to reality. Vitam Horm 37:243
76
SKINNER
590. Ying SY 1988 Inhibins, activins and follistatins: gonadal proteins
modulating the secretion of follicle-stimulating hormone. Endocr
Rev 9:267
591. Steinberger A, Steinberger E 1976 Secretion of an FSH inhibiting
factor by cultured Sertoli cells. Endocrinology 99:918
592. Bicsak TA, Vale W, Vaughan J, Tucker EM, Cappel S, Hsueh AJ
1987 Hormonal regulation of inhibin production by cultured Sertoli cells. Mol Cell Endocrinol 49:211
593. Morris PL, Vale WW, Cappel S, Bardin CW 1988 Inhibin production by primary Sertoli cell-enriched cultures: regulation by
follicle-stimulating hormone, androgens, and epidermal growth
factor. Endocrinology 122:717
594. Gonzales GF, Risbridger GP, de Kretser DM 1988 In vitro synthesis and release of inhibin in response to FSH stimulation by
isolated segments of seminiferous tubules from normal adult male
rats. Mol Cell Endocrinol 59:179
595. Conti M, Culler MD, Negro-Vilar A 1988 Adenosine receptordependent modulation of inhibin secretion in cultured immature
rat Sertoli cells. Mol Cell Endocrinol 59:255
596. Gonzales GF, Risbridger GP, de Kretser DM 1989 The effect of
insulin on inhibin production in isolated seminiferous tubule
segments from adult rats cultured in vitro. Mol Cell Endocrinol
61:209
597. Hsueh AJ, Dahl KD, Vaughan J, Tucker E, Rivier J, Bardin CW,
Vale W 1987 Heterodimers and homodimers of inhibin subunits
have different paracrine action in the modulation of luteinizing
hormone-stimulated androgen biosynthesis. Proc Natl Acad Sci
USA 84:5082
598. Lin T, Calkins JK, Morris PL, Vale W, Bardin CW 1989 Regulation of Leydig cell function in primary culture by inhibin and
activin. Endocrinology 125:2134
599. Sharpe RM, Kerr JB, Maddocks S 1988 Evidence for a role of the
Leydig cells in control of the intratesticular secretion of inhibin.
Mol Cell Endocrinol 60:243
600. Drummond AE, Risbridger GP, de Kretser DM 1989 The involvement of Leydig cells in the regulation of inhibin secretion by the
testis. Endocrinology 125:510
601. Roberts V, Meunier H, Sawchenko PE, Vale W 1989 Differential
production and regulation of inhibin subunits in rat testicular cell
types. Endocrinology 125:2350
602. Shaha C, Morris PL, Chen CL, Vale W, Bardin CW 1989 Immunostainable inhibin subunits are in multiple types of testicular
cells. Endocrinology 125:1941
603. Lee W, Mason AJ, Schwall R, Szonyi E, Mather JP1988 Secretion
of activin by interstitial cells in the testis. Science 243:396
604. van Dissel-Emiliani FM, Grootenhuis AJ, de Jong FH, de Rooij
DG 1989 Inhibin reduces spermatogonial numbers in testes of
adult mice and Chinese hamsters. Endocrinology 125:1899
605. Calkins JH, Sigel MM, Nankin HR, Lin T 1988 Interleukin-I
inhibits Leydig cell steroidogenesis in primary culture. Endocrinology 123:1605
606. Calkins JH, Guo H, Sigel MM, Lin T 1990 Differential effects of
recombinant interleukin-1 a and fi on Leydig cell function.
Biochem Biophys Res Commun 167:548
607. Kasson BG, Hsueh AJ 1986 Arginine vasopressin as an intragonadal hormone in Brattleboro rats: presence of a testicular vasopressin-like peptide and functional vasopressin receptors. Endocrinology 118:23
608. Awoniyi CA, Santuilli R, Sprando RL, Ewing LL, Zirkin BR 1989
Restoration of advanced spermatogenic cells in the experimentally
regressed rat testis: quantitative relationship to testosterone concentration within the testis. Endocrinology 124:1217
609. Awoniyi CA, Santulli R, Chandrashekar V, Schanbacher BD,
Zirkin BR 1989 Quantitative restoration of advanced spermatogenic cells in adult male rats made azoospermic by active immunization against luteinizing hormone or gonadotropin-releasing
hormone. Endocrinology 125:1303
610. Sun Y-T, Irby DC, Robertson DM, de Kretser D 1989 The effects
of exogenously administered testosterone on spermatogenesis in
intact and hypophysectomized rats. Endocrinology 125:1000
611. Santulli R, Sprando RL, Awoniyi CA, Ewing LL, Zirkin BR 1990
To what extent can spermatogenesis be maintained in the hypo-
612.
613.
614.
615.
616.
617.
618.
619.
620.
621.
622.
623.
624.
625.
626.
627.
628.
629.
630.
631.
632.
633.
Vol. 12, No. 1
physectomized adult rat testis with exogenously administered
testosterone? Endocrinology 126:95
Lording DW, de Kretser DM 1972 Comparative ultrastructural
and histochemical studies of the interstitial cells of the rat testis
during fetal and postnatal development. J Reprod Fertil 29:261
Tapanainen J, Kuopio T, Pelliniemi LJ, Huhtaniemi I 1984 Rat
testicular endogenous steroids and number of Leydig cells between
the fetal period and sexual maturity. Biol Reprod 31:1027
Prince FP 1984 Ultrastructure of immature Leydig cells in the
human prepubertal testis. Anat Rec 209:165
Teerds KJ, De Rooij DG, Rommerts FF, van der Tweel I, Wensing
CJ 1989 Turnover time of Leydig cells and other interstitial cells
in testes of adult rats. Arch Androl 23:105
Verhoeven G 1980 Androgen receptor in cultured interstitial cells
derived from immature rat testis. J Steroid Biochem 13:469
Anthony CT, Kovacs WJ, Skinner MK 1989 Analysis of the
androgen receptor in isolated testicular cell types with a microassay that uses an affinity ligand. Endocrinology 125:2628
Cunha GR 1973 The role of androgens in the epithelio-mesenchymal interactions involved in prostatic morphogenesis in embryonic mice. Anat Rec 175:87
Sugimura Y, Cunha GR, Donjacour AA 1986 Morphogenesis of
ductal networks in the mouse prostate. Biol Reprod 34:961
Sugimura Y, Cunha GR, Donjacour AA 1986 Morphological and
histological study of castration-induced degeneration and androgen-induced regeneration in the mouse prostate. Biol Reprod
34:973
Swinnen K, Cailleau J, Heyns W, Verhoeven G 1989 Stromal cells
from the rat prostate secrete androgen-regulated factors which
modulate Sertoli cell function. Mol Cell Endocrinol 62:147
Swinnen K, Cailleau J, Heyns W, Verhoeven G 1990 Prostatic
stromal cells and testicular peritubular cells produce similar paracrine mediators of androgen action. Endocrinology 126:142
Kerr JB, Donachie K, Rommerts FF 1985 Selective destruction
and regeneration of rat Leydig cells in vivo. A new method for the
study of seminiferous tubular-interstitial tissue interaction. Cell
Tissue Res 242:145
Molenaar R, de Rooij DG, Rommerts FF, Reuvers PJ, van der
Molen HJ 1985 Specific destruction of Leydig cells in mature rats
after in vivo administration of ethane dimethyl sulphonate. Biol
Reprod 33:1213
Morris ID, Phillips DM, Bardin CW 1986 Ethylene dimethanesulfonate destroys Leydig cells in the rat testis. Endocrinology
118:709
Verhoeven G, Cailleau J, Morris ID 1989 Inhibitory effects of
alkane sulphonates on the function of immature rat Leydig,
Sertoli and peritubular cells cultured in vitro. J Mol Endocrinol
2:145
Roberts KP, Griswold MD 1990 Ethylene dimethanesulphonate
inhibits the functions of Sertoli cells in culture at sublethal doses.
Endocrinology 126:1618
Kerr JB, Bartlett JM, Donachie K 1986 Acute response of testicular interstitial tissue in rats to the cytotoxic drug ethane dimethanesulphonate. An ultrastructural and hormonal assay study.
Cell Tissue Res 243:405
Kerr JB, Donachie K 1986 Regeneration of Leydig cells in unilaterally cryptorchid rats: evidence for stimulation by local testicular
factors. Cell Tissue Res 245:649
Bartlett JM, Kerr JB, Sharpe RM 1986 The effect of selective
destruction and regeneration of rat Leydig cells on the intratesticular distribution of testosterone and morphology of the seminiferous epithelium. J Androl 7:240
Kerr JB, Bartlett JM, Donachie K, Sharpe RM 1987 Origin of
regenerating Leydig cells in the testis of the adult rat. An ultrastructural, morphometric and hormonal assay study. Cell Tissue
Res 249:367
Risbridger GP, Kerr JB, de Kretser DM 1987 Influence of the
cryptorchid testis on the regeneration of rat Leydig cells after
administration of ethane dimethane sulphonate. J Endocrinol
112:197
Hardy MP, Zirkin BR, Ewing LL 1989 Kinetic studies on the
February, 1991
634.
635.
636.
637.
638.
639.
640.
641.
642.
643.
644.
645.
646.
647.
648.
649.
650.
651.
652.
653.
654.
655.
656.
CELL-CELL INTERACTIONS IN THE TESTIS
development of the adult population of Leydig cells in testes of
the pubertal rat. Endocrinology 124:762
Hardy MP, Kelce WR, Klinefelter GR, Ewing LL 1990 Differentiation of Leydig cell precursors in vitro: a role for androgen.
Endocrinology 127:488
Christensen AK, Gillim SW 1969 The correlation of fine structure
and function in steroid-secreting cells with emphasis on those of
the gonad. In: McKerns KW (ed) The Gonads. Appleton-CenturyCrofts, New York, p 415
Wing T-Y, Lin H-S 1977 The fine structure of testicular interstitial cells in the adult golden hamster with special reference to
seasonal changes. Cell Tissue Res 183:385
Miller SC, Bowman BM, Rowland HG 1983 Structure, cytochemistry, endocytic activity, and immunoglobulin (FC) receptors of
rat testicular interstitial-tissue macrophages. Am J Anat 168:1
Yee JB, Hutson JC 1983 Testicular macrophages: isolation, characterization and hormonal responsiveness. Biol Reprod 29:1319
Berg A 1985 Effect of cryptorchidism on the morphology of
testicular macrophages: evidence for a Leydig cell-macrophage
interaction. Int J Androl 8:86
Yee JB, Hutson JC 1985 Effects of testicular macrophage-conditioned medium on Leydig cells in culture. Endocrinology 116:2682
Wei RQ, Yee JB, Straus DC, Hutson JC 1988 Bactericidal activity
of testicular macrophages. Biol Reprod 38:830
Miller SC, Bowman BM, Roberts LK 1984 Identification and
characterization of mononuclear phagocytes isolated from rat
testicular interstitial tissues. J Leukocyte Biol 36:679
Niemi M, Sharpe RM, Brown WR 1986 Macrophages in the
interstitial tissue of the rat testis. Cell Tissue Res 243:337
el-Demiry MI, Hargreave TB, Busuttil A, Elton R, James K,
Chisholm GD 1987 Immunocompetent cells in human testis in
health and disease. Fertil Steril 48:470
Hedger MP, Eddy EM 1987 The heterogeneity of isolated adult
rat Leydig cells separated on Percoll density gradients: an immunological, cytochemical and functional analysis. Endocrinology
121:1824
Pollanen P, Niemi M 1987 Immunohistochemical identification
of macrophages, lymphoid cells and HLA antigens in the human
testis. Int J Androl 10:37
Pollanen P, Maddocks S 1988 Macrophages, lymphocytes and
MHC II antigen in the ram and rat testis. J Reprod Fertil 82:437
Head JR, Neaves WB, Billingham RE 1983 Immune privilege in
the testis. I. Basic parameters of allograft survival. Transplantation 36:423
Hedger MP 1989 The testis: an 'immunologically suppressed'
tissue? Reprod Fertil Dev 1:75
Tung KSK, Teuscher C, Meng AL 1981 Autoimmunity to spermatozoa and the testis. Immunol Rev 55:217
Johnson MH 1973 Physiological mechanisms for the immunological isolation of spermatozoa. Adv Reprod Physiol 6:279
Hedger MP, Qin J-X, Robertson DM, de Kretser DM 1990 Intragonadal regulation of immune system functions. Reprod Fertil
Dev 2:263
Born W, Wekerle H 1981 Leydig cells nonspecifically suppress
lymphoproliferation in vitro: implications for the testis as an
immunologically privileged site. Am J Reprod Immunol 2:291
Head Jr, Billingham RE 1985 Immune privilege in the testis. II.
Evaluation of potential local factors. Transplantation 40:269
Pollanen P, Soder O, Uksila J 1988 Testicular immunosuppressive
protein. J Reprod Immunol 14:125
Orava M, Centell K, Vihko R 1985 Human leukocyte interferon
inhibits human chorionic gonadotropin stimulated testosterone
657.
658.
659.
660.
661.
662.
663.
664.
665.
666.
667.
668.
669.
670.
671.
672.
673.
674.
675.
676.
77
production by porcine Leydig cells in culture. Biochem Biophys
Res Commun 127:809
Orava M, Voutilainen R, Vihko R 1989 Interferon-gamma inhibits
steroidogenesis and accumulation of mRNA of the steroidogenic
enzymes P450scc and P450cl7 in cultured porcine Leydig cells.
Mol Endocrinol 3:887
Mealy K, Robinson B, Millette CF, Majzoub J, Wilmore DW 1990
The testicular effects of tumor necrosis factor. Ann Surg 211:470
Free MJ 1977 Blood supply to the testis and its role in local
exchange and transport of hormones. In: Johnson AD, Gomes
WR (eds) The Testis. Academic Press, New York, vol 4:39
Kormano M 1968 Penetration of intravenous trypan blue into the
rat testis and epididymis. Acta Histochem 30:133
Kormano M 1973 Blood supply to testes and excurrent duct. Adv
Biosci 10:73
Setchell BP 1970 Testicular blood supply, lymphatic drainage,
and secretion of fluid. In: Johnson AD, Gomes WR, Vandemark
NL (eds) The Testis. Academic Press, New York, vol 4:101
Setchell BP 1990 Local control of testicular fluids. Reprod Fertil
Dev 2:291
Gospodarowicz D, Ferrara N, Schweigerer L, Neufeld G 1987
Structural characterization and biological functions of fibroblast
growth factor. Endocr Rev 8:95
Ueno N, Baird A, Esch F, Ling N, Guillemin R 1987 Isolation
and partial characterization of basic fibroblast growth factor form
bovine testis. Mol Cell Endocrinol 49:189
Story MT, Sasse J, Kakuska D, Jacobs SC, Lawson RK 1988 A
growth factor in bovine and human testes structurally related to
basic fibroblast growth factor. J Urol 140:422
Fawcett DW 1973 Observations on the organization of the interstitial tissue of the testis and on the occluding cell junctions in
the seminiferous epithelium. Adv Biosci 10:83
Fawcett DW, Heidger PM, Leak LV 1969 Lymph vascular system
of the interstitial tissues of the testis as revealed by electron
microscopy. J Reprod Fertil 19:109
Fawcett DW, Neaves WB, Flores MN 1973 Comparative observations on intertubular lymphatis and the organization of the
interstitial tissue of the mammalian testis. Biol Reprod 9:500
Bellve AR, Zheng W 1989 Growth factors as autocrine and paracrine modulators of male gonadal functions. J Reprod Fertil
85:771
Fauser BC, Baird A, Hsueh AJ 1988 Fibroblast growth factor
inhibits luteinizing hormone-stimulated androgen production by
cultured rat testicular cells. Endocrinology 123:2935
Raeside JI, Berthelon MC, Sanchez P, Saez JM 1988 Stimulation
of aromatase activity in immature porcine Leydig cells by fibroblast growth factor (FGF). Biochem Biophys Res Commun
151:163
Sordoillet C, Chauvin MA, Revol A, Morera AM, Benahmed M
1988 Fibroblast growth factor is a regulator of testosterone secretion in cultured immature Leydig cells. Mol Cell Endocrinol
58:283
Murono EP, Washburn AL 1990 Basic fibroblast growth factor
inhibits delta5-3j8-hydroxysteroid dehydrogenase-isomerase activity in cultured immature Leydig cells. Biochem Biophys Res
Commun 168:248
Jaillard C, Chatelain PG, Saez JM 1987 In vitro regulation of pig
Leydig cell growth and function: effects of fibroblast growth factor
and somatomedin-C. Biol Reprod 37:665
Skinner MK 1990 Mesenchymal (stromal)-epithelial interactions
in the testis and ovary which regulate gonadal function. Reprod
Fertil Dev 2:237