Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
Brad J. Martinsen, Ph.D.
Department of Pediatric Cardiology
Phone: 625-2976
Email: marti198@umn.edu
Larsen's Human Embryology
Week One
Origin of the germ line
Gametogenesis: Male + Female
Fertilization and cleavage
I. Origin of the germ line.
Studies of the mechanisms that underlie human gametogenesis provide a basis for
understanding chromosome anomalies, contraceptive techniques, and assisted
reproduction.
A. Migration of the primordial germ cells.
1. Cells that give rise to the gametes originate within the primary ectoderm during
the second week of development. They then detach from the ectoderm and
migrate into the yolk sac (Timeline, pg2).
2. At first they are seen as a mass of extraembryonic mesoderm at the caudal end
of the embryo and then within the endoderm of the yolk sac. These cells are
called the primordial germ cells, and their lineage constitutes the germ line (Fig.
1-1A).
B. During the fourth week, the primordial germ cells migrate into the posterior body wall
of the embryo from the yolk sac (Fig 1-1B).
1. The primordial germ cells continue to multiply by mitosis during their migration.
2. In the dorsal body wall, these cells come to rest on either side of the midline in
the loose mesenchymal tissue adjacent to the tenth thoracic vertebrae level that
will form the gonads.
3. The germ cells then induce the adjacent coelonic epithelium and mesonephros to
proliferate and form the primitive sex cords. This creates a swelling (genital
ridges/primordial gonads) medial to each mesonephros on either side of the
vertebrae column.
4. Teratoma: stray germ cells can get stranded along the route of migration at
inappropriate sites in the dorsal body wall. These cells can eventually give rise to
a tumor.
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
5. Cortical sex cords nourish and regulate the development ovarian follicles in
females.
6. Medullary sex cords nourish and regulate the development of the sertoli cells in
males (Fig 1-1C).
II. Gametogenesis.
The process of meiosis and cytodifferentiation converts germ cells into mature male
and female gametes (Fig 1-3, review Fig 1-2 and Table 1-1 if necessary).
A. Spermatogenesis.
1. At puberty, the testes begin to secrete greatly increased amounts of
testosterone. This triggers maturation of the seminiferous tubules, and the
commencement of spermatogenesis (Fig 1-4).
2. Primordial germ cells resume development and divide several times by mitosis,
producing spermatogonia (Fig 1-4A).
3. Migratory phase !primary spermatocytes ! 1st meiotic divisions ! two
secondary spermatocytes ! 2nd meiotic division ! 4 spermatids.
4. Spermiogenesis: tubulobulbar complexes transfer excess cytoplasm to the
sertoli cells, causing changes in shape and internal organization that transform
them into spermatozoa.
5. Spermiation : last connections with sertoli cells break, releasing the spermatozoa
into the tubule lumen.
6. Capacitation : the final step of sperm maturation takes place in the female genital
tract and requires contact with the secretions of the oviduct. Spermatozoa used
in in-vitro fertilization procedures are artificially capacitated.
Summary: spermatogenesis 64 days:
16 days for sprematogonial mitosis
8 days for 1st meiotic division
16 days for 2nd meiotic division
24 days for spermiogenesis
final step is capacitation
Clinical Note: Offspring of older men have an increased incidence of
achondroplasia (a congenital skeletal anomaly characterized by retarded bone
growth).
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
B. Oogenesis is discontinuous and begins during fetal life.
1. At 5 months of fetal life the total number of primary oocytes have been produced
in the ovaries.
2. 12 weeks development ! a proportion of the several million oogonia in the
genital ridges enters the first meiotic prophase and then almost immediately
becomes dormant. The follicle cells derived from the sex cord cells enclose the
primary oocyte, constituting the primordial follicle. By puberty only 400,000 of 7
million remain.
3. Female puberty ! the rising levels of pituitary gonadotropins (FSH + LH)
regulate later phases of folliculogenesis in the ovary and the proliferative phase
in the uterine endometrium.
4. 5-12 primary oocytes become growing follicles. Some of the growing follicles
degenerate while others continue to respond to the rising level of FSH by taking
up fluid and developing a central fluid filled cavity called the antrum. Thus it is
now called an antral follicle. Eventually one of the growing follicles gains primacy
while the others degenerate. The mature graafian follicle continues to enlarge by
absorbing fluid, but at this point the oocyte still has not resumed meiosis (Figure
1-6).
5. The ovulatory surge (about day 15 or 14 of the menstrual cycle) of FSH + LH
stimulates the primary oocyte of the remaining mature graafian follicle to resume
meiosis. The cell division forms the secondary oocytes and the first polar body
(Fig 1-8B).
6. The secondary oocyte promptly beings the second meiosis division, but is
arrested at the second meiotic metaphase (about 3 hours before ovulation).
7. Ovulation occurs about 38 hours after the beginning of the ovulatory surge of
FSH and LH. A combination of tension produced by smooth muscle cells in the
follicle wall, plus the release of collagen-degrading enzymes, cause the follicle to
rupture in a non-explosive process. Subsequently, the sticky mass formed by the
oocyte and cumulus is actively scraped off the surface of the ovary by the
fimbriated mouth of the oviduct. The beating cilia move the oocyte to the ampulla
of the oviduct (Fig 1-9).
8. The oocyte is viable for as long as 24 hours. (Clinical side bar: prevention of
ovulation with progesterone interferes with the release of FSH and LH).
Clinical Note: Since all of the primary oocytes are formed by month 5 of fetal life the
incidence of trimsomy 21 (Down Syndrome) increases with advanced age of the
mother.
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
C. Chromosomal anomalies that arise during gametogenesis.
1. 1/3 of all conceptions in healthy women abort spontaneously. Chromosomal
anomalies cause about 40% to 50% of them.
2. The chromosomal anomalies that allow embryos to survive result in infants with a
variety of disorders such as Down Syndrome.
3. Abnormal chromosomes can be produced by an error in meiosis, fertilization, or
mitosis. The gametes or blastomeres that result from these errors contain
missing or extra chromosomes, or chromosomes with duplicated, deleted, or
rearranged segments.
4. Monosomy: results from the fusion of a normal gamete with another that is
missing a specific chromosome. Example: monosomy 21 ! these embryos die
rapidly during embryonic development.
5. Trisomy: results from the fusion of a normal gamete with another that has two of
the same kind of chromosome (Fig 1-14 and Fig 1-16). Trisomy 21, Down
Syndrome, results in individuals that exhibit congenital heart defects, mental
retardation, and propensity to development leukemia. 95% of Down Syndrome
arises through nondisjunction in that maternal germ line. Can an individual with
Down Syndrome produce normal offspring? Yes, meiosis of a trisomic germ cell
yields gametes with a normal single copy of the chromosome as well as
abnormal gametes with two copies.
III. Fertilization and first days of development.
A. Fertilization (occurs in the ampulla of the uterine tube):
1. Sperm binding occurs through the interaction of sperm glycosyltransferases and
the ZP3 receptors located on the Zona Pellucida
2. The fusion of the spermatozoon cell membrane (aided by acrosomal
enzymes!acrosin) with the oocyte membrane causes the mechanism (cortical
reaction) that prevents polyspermy, as well as causing the oocyte to resume
meiosis (Fig 1-10). The sperm mitochondria and tail degenerate.
3. The secondary oocyte completes the second meiotic metaphase and anaphase
producing another polar body. The first polar body simultaneously completes its
second meiotic division. The oocyte is now considered to be a definitive oocyte.
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
4. The female and male pronuclei fuse, forming the diploid and 2N nucleus of the
fertilized zygote. This is the zero time point of embryonic development (Fig 110C). Ploidy refers to the number of copies of each chromosome present in the
nucleus. N number refers to the number of copies of each unique doublestranded DNA molecule in the nucleus. Clinical side bar: antiprogesterone
compound RU-486 is an abortifacient.
B. First days of development.
As the zygote travels down the oviduct it undergoes cleavage without increasing its
size. This subdivides the large zygote into many smaller daughter cells called
blastomeres.
24 Hours: First cleavage (Fig 1-11 and 1-12)
48 Hours: Second cleavage
3 Days:
Embryo consists of 6 to 12 cells, reorganization
(compaction!
!Uvomorulin, a glycoprotein found on the surface of
blastomeres, is involved in compaction) of the blastomeres, starts at the 8
cell stage. The centrally placed blastomeres are now called the inner cell
mass (they give rise to most of the embryo proper, which is also called the
embryoblast). The blastomeres at the periphery constitute the outer cell
mass, they are the primary source for the membranes of the placenta. It
is also refered to as the trophoblast.
4 Days:
Embryo consists of 16 to 32 cells called morula.
5 Days:
The embryo is now called a blastocyst. A large cavity called the
blastocyst cavity forms due to the hydrostatic pressure. The embryoblast
cells form a compact mass at one side of the cavity (embryonic pole),
while the trophoblast is organized into a thin, single-layered epithelium
(Fig 1-11).
6 Days:
Blastocyst implants into the uterine wall (Fig 1-13). The blastocyst
hatches from the zona pellucida before implanting. The trophoblast at the
embryonic pole differentiates to produce the syncytiotrophoblast, and
begins to implant the blastocyst into the uterine endometrium.
Some of the proliferating trophoblast cells lose their membranes and form
a syncytium. The trophoblast cells, which form the wall of the blastocyst,
retain their cell membranes and constitute the cytotrophoblast (Fig 2-1).
Ectopic pregnancy results when a blastocyst implants in the peritoneal cavity on the
surface of the ovary, within the oviduct, or at an abnormal site in the uterus. Because
the blood vessels at abnormal implantation sites are apt to rupture, ectopic pregnancy is
often revealed by symptoms of abdominal pain and/or vaginal bleeding.
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
Week Two
I. Days 8-9
A. The embryoblast consists of an external layer called the epiblast (primary
ectoderm) and an internal layer called the hypoblast (primary endoderm). The
resulting two-layered embryoblast is called the bilaminar germ disc (Fig 2-2).
B. As implantation progresses, the expanding syncytiotrophoblast gradually
envelops the blastocyst (Fig 2-3).
C. A layer of epiblast cells is gradually displaced toward the embryonic pole by
accumulating fluid. These cells differentiate into amnioblasts, which form the
amniotic membrane. The newly formed cavity is called the amnion (Fig 2-3).
D. Cells at the periphery of the hypoblast begin to migrate out over the inner surface
of the cytotrophoblast. Eventually, these migrating hypoblast cells completely
line the former blastocyst cavity.
II. Days 10-15
A. This new membrane is now called the exocoelomic membrane or Heuser’s
membrane (Fig 2-4).
B. The former blastocyst cavity is now called the primary yolk sac or exocoelomic
cavity (Fig 2-4).
C. Once the primary yolk sac is formed, a thick, loosely reticular layer of cellular
material called the extraembryonic reticulum is secreted between Heuser’s
membrane and the cytotrophoblast.
D. Extraembryonic mesoderm cells that arise from the epiblast at the caudal end of
the bilaminar germ disc begin to migrate out. Two layers result--one coating the
outer surface of Heuser’s membrane and the other lining the inner surface of the
cytotrophoblast (Fig 2-4B).
E. Eventually the extraembryonic reticulum trapped between the two layers of
extraembryonic mesoderm breaks down and is replaced by fluid, forming the
chorionic cavity (Fig 2-4C and Fig 2-5A).
F. The growth and migration of the extraembryonic mesoderm gradually separates
the amnion from the cytotrophoblast.
G. On day 12, a second wave of proliferation in the hypoblast produces a new
membrane that migrates out over the inside of the extraembryonic mesoderm,
pushing the primary yolk sac in front of it. This new layer becomes the
endodermal lining of the definitive (secondary) yolk sac (Fig 2-5A-C).
H. As the definitive yolk sac develops on day 13 the primary yolk sac breaks up into
disintegrating exocoelomic vesicles (Fig 2-5C and Fig 2-6).
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
I. By 14-15 days the bilaminar germ disc has formed and is suspended in the
chorionic cavity by a thick connecting stalk.
J. The extraembryonic mesoderm forming the outer layer of the yolk sac wall is a
major site of hematopoiesis. Cells from the primary ectoderm migrate into the
yolk sac forming the first endothelial cells and hematopoietic stem cells. The
coordinated development of these cells into the vitelline vasculature is called
blood island formation.
K. Meckel’s diverticulum: The yolk sac normally disappears before birth, but if it
persists a digestive tract anomaly may develop.
III. Uteroplacental circulatory system (9-21 days)
A. The uteroplacental circulation is the system by which maternal and fetal blood
flowing through the placenta come into close contact and exchange gases and
metabolites by diffusion.
B. The system starts to form on day 9 as the trophoblastic lacunae open within the
synctiotrophoblast. Eventually, they anastomose (blood vessels join either endto-end or side-to-side) with maternal capillaries.
C. By days 11 and 13 extensions of cytotrophoblast grow out into the blood-filled
lacunae, carrying with them a covering of syncytiotrophoblast, forming the
primary stem villi. (Fig 2-7A).
D. On day 16 the extraembryonic mesoderm associated with the cytotrophoblast
penetrates the core at the primary stem villi. The resulting villi are now called
secondary stem villi. (Fig 2-7B).
E. By 21 days the tertiary stem villi have formed. The villous mesoderm has given
rise to blood vessels that connect with the vessels forming in the embryo proper.
This establishes the working uteroplacental circulation (Fig 2-7C).
IV. Clinical Applications
A. Human chorionic gonadotropin (hCG):
1. is produced by the syncytiotrophoblast.
2. enters maternal blood circulation.
3. prevents degeneration of the corpus luteum and stimulates production of
progesterone.
4. can be assayed in maternal blood at day 8 after fertilization and in maternal
urine at day 10. This is the basis of early diagnosis of pregnancy.
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
B. Oncofetal antigens:
1. are cell surface antigens that normally appear only on embryonic cells but for
unkown reasons reexpress themselves in human malignant cells.
2. Monoclonal antibodies directed against these antigens is an avenue for
cancer therapy.
3. Examples: Carcinoembryonic antigen (CEA) is associated with colorectal
carcinoma. Alpha-fetalprotein is associated with hepatoma and germ cell
tumors.
C. RU-486 (Mifepristone):
1. will initiate menstruation when taken within 8-10 weeks of the previous
menses.
2. The conceptus will be sloughed along with the endometrium.
3. Is used in conjunction with prostaglandin and is 96% effective at terminating
pregnancy.
D. Complete hydatidiform mole: a pregnancy without an embryo. The conceptus
consists only of placental membranes. A normal diploid karyotype is observed,
but all the chromosomes are derived from the father (Fig 2-8 and 2-9).
1. If they do not abort symptoms of hypertension, edema, and vaginal bleeding
may exist in the mother.
2. Mole remnants are readily diagnosed on the basis of an abnormally high level
of plasma human chorionic gonadotropin (hCG).
3. Persistent trophoblastic disease: mole remnant grows to form a tumor. These
can also turn into a metastatic choriocarcinoma.
E. Partial hydatidiform moles (Fig 2-10).
1. Triploid, with a double dose of paternal chromosomes.
2. Symptoms are milder and slower to develop.
3. Tumors that arise are usually benign.
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
F. Genomic Imprinting:
1. Cytogenetic analysis of hydatidiform moles suggests that the paternal genetic
complement is responsible for the early development of the placenta and that
the maternal genetic complement is responsible for the early development of
the embryo.
2. These roles were studied using mouse oocytes that contain either two male
or two female pronuclei.
3. Methylation of DNA is a mechanism that leads to the independent expression
of maternal and paternal genomes during early development. The female
germ line is more highly methylated than the DNA of the male germ line. The
methylation of some genes (such as, H19, IGF2, IGF2r, MASH2, WT1) may
lead to their silencing while others may be activated by methylation.
4. The pattern of inheritance of a deletion in a specific region of a human
chromosome (15?) causes Prader-Willi Syndrome (floppy (hypotonic) infants,
low IQ, limb defects, uncontrollable hunger and subsiquent morbid obesity)
when the chromosome is inherited from the father. But causes a
phenotypically distinct condition, Angelman Syndrome (low IQ, seizures,
protruding tungue, and excessively happy), when the chromosome is
inherited from the mother.
5. The severity and age of onset of several genetic diseases (such as,
Huntington's, Chorea, Nf I and NF II, Wilm's tumor, Beckwith-Wiedemann
Syndrome, spinocerebellar ataxia, myotonic dystrophy) differ depending on
the parent from whom the mutated gene is inherited.
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
Week Three
Gastrulation & Neurulation
I. Gastrulation and the initial development of the somites and neural tube.
A. Primitive Streak.
1. Between days 15 and 16 the primitive streak forms. It starts out as a faint groove
at the caudal end of the bilaminar germ disc. Eventually it deepens forming a
primitive groove with a depression (primitive pit) at the cranial end. The mound
of epiblast cells surrounding the pit is called the primitive node (Fig 3-1).
2. The fundamental cranial/caudal, left/right, and ventral/dorsal axes are
established at this time.
B. Formation of definitive endoderm and intraembryonic mesoderm (process of
gastrulation).
1. On day 16, epiblast cells near the primitive streak proliferates and migrates
through the primitive streak into the space between the epiblast and hypoblast.
Some of the cells displace the entire hypoblast forming a new layer called the
definitive endoderm. It gives rise to the lining of the future gut and gut derivatives
(Fig 3-2).
2. Other epiblast cells diverge into the space between the epiblast and the nascent
definitive endoderm to form a third layer, the intraembryonic mesoderm(Fig 3-2).
3. Mesoderm cells that ingress through the primitive node migrate cranially to form
the prechordal plate and notochordal process(Fig 3-3). The notochordal
process is initially formed as a hollow mesodermal process and then
transformed into a solid notochord between days 16 and 22 (Fig 3-7). During
the transformation period the notochord process fuses with the endoderm. This
allows the yolk sac cavity to transiently communicate with the amniotic cavity
through an opening at the primitive pit called the neurenteric canal. During the
transformation process, some cells of endodermal origin may become
incorporated into the notochord.
4. Mesoderm cells that ingress through the primitive groove migrate to form the
mesoderm lying on either side of the midline (Fig 3-6 and Fig 3-7).
Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
5. The epiblast at this point takes on a new name, the ectoderm. Thus all three
layers of the trilaminar germ disc (the ectoderm, mesoderm and definitive
endoderm) were formed from the epiblast.
6. The buccopharyngeal membrane breaks down eventually to form the opening to
the oral cavity, while the cloacal membrane disintegrates to form the openings of
the anus and the urinary and genital tracks.
C. Paraxial, intermediate, and lateral plate mesoderm.
1. As the primitive streak regresses, the mesoderm cells that migrated laterally
begin to form cylindrical structures called the paraxial, intermediate and lateral
plate mesoderm on either side of the notochord (Fig 3-8).
2. Paraxial Mesoderm ! Somitomers (Fig 3-9)!
! somites (Fig 3-10, 3-11, and 312) !axial skeleton, voluntary musculature and part of the dermis. The fist 7
somitomeres do not go on to form somites. Instead, they give rise to the muscles
of the face, jaw, and throat.
Intermediate Mesoderm ! urinary system and genital system (Fig 3-10 and Fig 3-12).
Lateral Plate Mesoderm ! splits into the splanchnopleuric mesoderm (sometimes
refered to as intraembryonic visceral mesoderm!becomes the mesothelial covering of
the visceral organs) and somatopleuric mesoderm (sometimes refered to as
intraembryonic somatic mesoderm!gives rise to the lining of the body wall, parts of the
limbs, and dermis) (Fig 3-8).
D. Induction of the neural plate.
1. The axial mesoderm (prechordal and notochordal plate) induces the overlying
ectoderm to form the neural plate (Fig 4-8).
2. Formation of the neural tube begins on day 22 at the level of the first five somites
(Fig 4-9).
3. Closure of the cranial neuropore is bidirectional, and final closure occurs in the
area of the future forebrain.
4. Closure of the caudal neuropore is craniocaudal and finishes at the level of the
second sacral segment (the level of somite 31).
5. During neurulation neural crest cells begin to migrate in a craniocaudal wave
(beginning on day 22). Cephalic neural crest cells detach and migrate before
closure of the cranial neural tube. In contrast, trunk neural crest cells detach as
the lateral lips of the neural tube fuse (Fig 4-13).
Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
6. Neural crest cells are an extremely important population of cells that migrate into
the embryo to form a variety of structures (Fig 4-12 & 4-14).
For example: Odontoblasts arise from the neural crest. Neural crest cells that give
rise to Odontoblasts stop migrating and settle down against the buccal epithelium at
locations of the future teeth. Teeth are composite structures made up of the outer white
enamal which covers the teeth above the gums and the inner dentine, a different
mineralized tissue forming the root and interior of the teeth. Dentine and enamel are
extracellular products of two different types of cells, the ameloblasts (enamel) and
odontoblasts (dentine).
E. Clinical Applications.
1. Many of the malformations (like Sirenomelia) of caudal dysplasia (Fig 3-15)
seem to be related to the defects in the growth and migration of mesoderm
during the third week (gastrulation).
2. The short-tail brachyuric and tailless anuric mouse mutants display a range of
mesodermal defects and disruptions of gastrulation and notochord development
that are very similar to the abnormalities observed in human caudal dysplasia.
The expression of the T gene protein in the primitive streak and gastrulation
mesoderm makes it clear how a mutation in the gene could cause severe caudal
dysplasia.
3. Malformations of neural tube closure.
Spina Bifida Occulta: The mildest form of spina bifida may occur anywhere
along the spinal cord, but is most common at lower lumbar and sacral levels.
The vertebral arches of a single vertebra fail to fuse while the underlying neural
tube differentiates normally and does not protrude from the vertebral canal (Fig
4-18).
Meningomyelocele: More severe cases of spina bifida result in the protrusion
of neural tissue and meninges (Fig 4-19).
Anencephaly: This defect involves only the cranial neural tube and results in an
exposed dorsal mass of undifferentiated neural tissue (Fig 4-20A).
Inionschisis: Failure of the neural tube to properly differentiate and close in the
occipital and upper spinal regions (Fig 4-20B).
Rieger Syndrome: Embryological disturbance of the neural crest ectoderm
results in severe enamel hypoplasia, conical and misshapen teeth, hypodontia,
hyperdonita, and impactions. Abnormalities of migration along the buccal
epithelium results in ectopism.
Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
4. Meningohydroencephalocele: This anomaly may form through defective
ossification of the occipital bone (not due to defective NT closure) (Fig 4-21).
5. Sacrococcygeal teratoma:
a. the remnants of the primitive streak causes the formation of a tumor.
b. The tumor is derived from pluripotent cells, thus it contains various types of
tissues (bone, nerve, hair,…)
c. Occurs more commonly in female infants
d. Becomes malignant during infancy and must be removed by age 6 months.
6. Chordoma:
a. The remnants of the notochord causes the formation of a tumor.
b. Found either intracranially or in the sacral region.
c. More common in men (age 50)
d. Either benign or malignant.
Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
Musculoskeletal System
I. Role of somites in the formation of the vertebrae and musculature of the
developing embryo.
A. Somites subdivide into three kinds of mesodermal primordium (Fig 4-1 and 4-6).
1. Dermatomes: form the dermis of the scalp, neck and trunk.
2. Myotomes: form the segmental musculature of the back and the anterolateral
body wall.
3. Sclerotomes: surround the notochord and neural tube and eventually form the
vertebral bodies and vertebral arches and also contribute to the base of the skull.
The costal processes that appear on the vertebral bodies in the thoracic region
go on to form the ribs.
Defective induction of vertibral bodies on one side of the body may result in what
medical condition?
II. Vertebral Column.
A. Vertebrae in general.
1. Mesodermal cells from the sclerotome migrate and condense around the
notochord to form the centrum, around the neural tube to form the vertebral
arches, and in the body wall to form the costal processes .
2. Centrum forms the vertebral body.
3. Vertebral arches form the pedicles, laminae, spinous process, articular
processes, and the transverse processes.
4. Costal processes form the ribs.
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
B. Intersegmental position of the vertebrae (Fig 4-2, and Fig 4-3).
1. As mesodermal cells from the sclerotome migrate towards the notochord and
neural tube, they split into a cranial portion and a caudal portion.
2. The caudal portion of each sclerotome fuses with the cranial portion of the
succeeding sclerotome, which results in the intersegmental position of the
verebra.
3. The splitting of the sclerotome is important because if allows the developing
spinal nerve a route of access to the myotome that it must innervate.
C. Joints of the vertebral column.
1. Synovial joints.
a) Located in the occipital and upper cervical vertebra.
2. Secondary cartilaginous joints (symphyses) (Fig 4-4).
a) Are the joints between the vertebral bodies in which the intervertebral disks
play a role.
b) An intervertebral disk consists of a Nucleus pulposus and an Annulus
fibrosus.
c) The Nucleus pulposus is a remnant of the embryonic notochord. By 20
years of age, all notochordal cells have degenerated such that all notochordal
vestiges in the adult are limited to just a noncellular matrix.
d) The Annulus fibrosus is an outer rim of fibrocartilage derived from
mesoderm found between the vertebral bodies.
D. Clinical Applications.
1. Intervertebral disk herniation is a prolapse of the nucleus pulposus through the
defective annulus fibrosus into the vertebral canal. The nucleus pulposus
impinges on spinal roots and results in root pain.
2. Spina bifida occulta (as mentioned in the previous lecture) results from failure
of the vertebral arches to form or fuse.
3. Spondylolisthesis occurs when the pedicles of the vertebral arches fail to fuse
with the vertebral body.
4. Hemivertebrae occurs when wedges of vertebrae appear that are usually
situated laterally between two other vertebrae.
5. Vertebral bar results when there is a localized failure of segmentation on one
side of the column, usually in a posterolateral site.
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Dr. Martinsen
DENT 5315/OBIO-8024
January 16, 2007
6. Block vertebra results when there is a lack of separation between two or more
vertebrae, usually occurring in the lumbar region.
7. Cleft vertebra occurs when a cleft develops in the vertebra, usually in the
lumbar region.
8. Idiopathic scoliosis is a lateral deviation of the vertebral column (both deviation
and rotation of vertebral bodies).
E. Ribs.
1. Ribs develop from costal processes, which form at all vertebral levels. However,
only costal processes in the thoracic region grow into ribs.
2. The first seven ribs connect ventrally to the sternum via the costal cartilages and
are called the true ribs. The five lower ribs do not articulate directly with the
sternum and are called false ribs (Fig 4-5).
3. Clinical note: Acessory lumbar ribs are the most common. Acessory
cervical ribs are attached to the C7 vertebrae and may put pressure on the
lower trunk of the brachial plexus and subclavian artery, causing superior
thoracic outlet syndrome.
F. Sternum.
1. The sternum develops from two sternal bars that form in the ventral body wall
independent of the ribs and clavicle.
2. The sternal bars fuse with each other in a cranial-caudal direction to form the
manubrium, body, and xiphoid process (does not ossify until birth) (Fig 4-5).
3. Clinical note: A sternal cleft occurs when the sternal bars do not fuse
completely. It is fairly common and if small is generally of no clinical
significance.The Pectus excavatum (funnel chest) is the most common chest
anomaly consisting of a depression of the chest wall. These individuals
demonstrate cardiopulmonary restriction, drooped shoulders, and scoliosis.
Surgical intervention is usually required.
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Skeletal Muscle.
A. Head and neck musculature.
1. Is derived from somitomeres 1-7 of the head and neck region which participate in
the formation of the pharyngeal arches.
2. Extraocular muscles are derived from somitomeres 1,2,3, and 5. Somitomeres
1,2, and 3 are called preotic myotomes (somites).
3. Tongue muscles are derived from the myotomes in the occipital region.
B. Trunk musculature.
1. Is derived from myotomes in the trunk region that partition into dorsal epimeres
and ventral hypomeres (Fig 4-6).
2. Epimeres develop into the intrinsic back muscles (erector spinae).
3. Hypomeres develop into the prevertebral, intercostal, and abdominal muscles.
IV.
Limb Skeleton and Musculature Development.
A. Inductive interactions that form the limb.
1. Somites induce the formation of limb buds in the somatopleuric lateral plate
mesoderm.
!24 days: the upper limb bud appears in the lower cervical region (Fig 11-1A&B).
!28 days: the lower limb bud appears in the lower lumbar region.
2. Apical ectodermal ridge induces the differentiation of the limb buds (Fig 111C&D).
3. The late-formed mesenchyme at the tip of the limb bud differentiates into the
distal segments of the limb (Fig 11-2).
4. The early-formed mesenchyme at the base of the bud differentiates into the
proximal segments of the limb (Fig 11-2).
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B. Differentiation of the limb bud (5th to 8th weeks of development) (Fig 11-3).
The upper limbs develop in advance of the lower limbs, but by the end of limb
development the two limbs are nearly synchronized.
Day 33!
! Upper limb: hand plate, fore-arm, arm, and shoulder regions can be
distinguished.
Lower limb: the tappering distal tip (eventually forms the foot) can be
distinguished.
Day 37!
! Upper limb: carpal region and digital plate have formed in the hand plate.
Lower limb: thigh, leg, and foot have become distinct.
Day 38!
! Upper limb: the tips of the digital rays project slightly, producing a
crenulated rim on the digital plate. Programmed cell death takes place
in the radial necrotic zones between the digital rays. This process will
gradually sculpt the digital rays out of the digital plate to form the fingers
and toes.
Lower limb: has increased in length and has formed a defined foot plate.
Day 44!
! Upper limb: the margin of the digital plate is deeply notched and the
grooves between the digital plate is deeper. The elbow has formed.
Lower limb: Toe rays are visible in the digital plate of the foot, but the rim
of the plate is not crenulated.
Day 47!
! Upper limb: has undergone horizontal flexion.
Lower limb: has started to flex and the toe rays are more prominent
(digital plate is still smooth).
Day 52!
! Upper limb: is slightly bent at the elbows. The fingers have developed
distal swellings called tactile pads. The hands are slightly flexed at the
wrists and meet at the midline.
Lower limb: is longer and the feet have begun to approach each other at
the midline. The rim of the digital plate is notched.
Day 56!
! Upper limb & Lower limb: arms and legs are well defined. The fingers of
the two hands overlap at the midline. Toes are fully developed.
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C. Somite, lateral plate mesoderm, and neural crest contribution to the limb.
1. Lateral plate mesoderm gives rise to the bones, tendons, ligaments, and
vasculature of the limbs.
2. Somitic mesoderm that migrates into the developing limb gives rise to the
musculature (Fig 11-5).
3. Neural Crest Cells that migrate into the limb give rise to melanocytes and
Schwann cells.
Note: The quail-chick chimera system was used to study the cell populations that
give rise to the various elements of the limbs.
D. The process of endochondral ossification forms the limb bones via a
cartilaginous precursor (Fig 11-6).
1. The axial mesenchymal condensation is a rodlike condensation of lateral plate
mesenchyme that forms along the long axis of the limb bud.
2. Chondrocytes within this region respond to growth factors and begin to
differentiate, releasing extracellular matrix molecules (collagen type II and
proteoglycans).
3. The initial phase of chondrification results in the perichondrium. This
deposition of cartilage around the entire axial mesenchymal condensation forms
a cartilaginous envelope.
4. The chondrifying bone primordia will go on to form a cartilaginous model of
each limb bone while the mesenchyme of the interzone forms the fibroblastic
tissue of the presumptive joint.
5. After the limb bone has chondrified the process of ossification starts in the
primary ossification center.
6. First mesenchymal cells in the perichondrium respond to growth factor-Beta-like
molecules and differentiate into osteoblasts (bone cells). These cells secrete
the calcium salt matrix of minearlized bone, forming a primary bone collar
around the circumference of the bone.
7. The osteoclasts break down previously formed bone to remodel the growing
limb bones.
8. Eventually even the cartilaginous core enclosed by the primary bone collar also
begins to ossify, forming a loose trabecular network of bone.
9. At birth, the diaphyses (shafts of the limb bones consisting of a bone collar and
trabecular core) are completely ossified, while the end of the bones (epiphyses)
are still cartilaginous.
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10. After birth, secondary ossification centers develop in the epiphyses, which
gradually ossify.
11. The epiphyseal cartilage plate (growth plate or physis) persists between the
epiphysis and the metaphysis ( the growing end of the diaphysis). The
continued proliferation of the chondrocytes allows the diaphysis to lengthen
during development. When the bones have stopped growing the epiphyses and
diaphyses fuse.
E. The timeline of limb bone formation.
1. 5th week!
! axial mesenchyme of the limb buds begins to condense. The bones
of the UPPER LIMB form slightly earlier than the LOWER LIMB.
2. End of 5th week!
! the axial mesenchymal condensation that will give rise to
the proximal bones(scapula and humerus in the UPPER LIMB; the pelvic bones
and femur in the LOWER LIMB) is distinct.
3. Early 6th week!
! the mesenchymal precursor of the distal limb skeleton is
distinct in the UPPER AND LOWER LIMBS, and chondrification commences in
the humerus, ulna, and radius.
4. Middle of 6th week!
! In LOWER LIMB, the femur, the tibia, and, to a lesser
extent, the fibula begin to chondrify.
5. End of 6th week!
! the carpal and metacarpal bones of the UPPER LIMB and
the tarsals and metatarsals of the LOWER LIMB begin to chondrify.
6. Early 7th week!
! all the bones of the UPPER LIMB except the distal phalanges
of the second to fifth digits are undergoing chondrification. Primary ossification
centers begin to appear. Ossification has commenced in the clavicle.
7. End of 7th week!
! the distal phalanges of the HAND and all the bones of the
LOWER LIMB (except the distal row of phalanges) have begun to chondrify.
Humerus, radius, and ulna have begun ossification.
8. 8th week!
! The distal phalanges of the toes chondrify. Ossification begins in
the femur and tibia.
9. 9th week!
! The scapula and ilium begin to ossify.
10. 10th-14th weeks!
! Metacarpals, metatarsals, distal phalanges, proximal
phalanges, and middle phalanges begin to ossify.
11. 15th week!
! The ischium begins to ossify.
12. 16th week!
! Ossification of the calcaneus begins.
13. 20th week!
! The pubis begins to ossify.
14. Early Childhood!
! Smaller carpal and tarsal bones finally ossify.
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Note: Intramembranous ossification occurs in the embryo when mesoderm
condenses into sheets of highly vascular connective tissue, which then directly
forms a primary ossification center. The frontal bone and the parietal bones are
examples of bones that undergo intramembranous ossification. All bones of both
the Upper and Lower limbs undergo endochondral ossification. The clavicle,
however, undergoes both membranous and endochondral ossification.
F. Development of the diarthrodial (synovial) joints connecting the limb bones (Fig
11-6).
1. First, as mentioned earlier, the mesenchyme of the interzones between the
chondrifying bone primordia differentiates into fibroblastic tissue
(undifferentiated connective tissue).
2. The fibroblastic tissue of the presumptive joint differentiates into three layers: a
cartilage layer at the outer end of the future joint, and a central layer of dense
connective tissue. The central layer gives rise to the internal elements of the
joint.
3. The central layer condenses at the proximal and distal regions to form the
synovial tissue. This will eventually line the joint cavity.
4. The central zone of the central layer gives rise to the menisci and to enclosed
joint ligaments.
5. Vacuoles appear within the central zone, eventually coalescing to form the
synovial cavity. The joint capsule arises from the mesenchymal sheath
surrounding the entire interzone.
Note: The synchondroidal joints of the pelvis bones develop from interzones, but
the interzone mesenchyme simply differentiates into a single layer of fibrocartilage.
G. Limb musculature development.
1. During the fifth week, somitic mesoderm invades the limb bud and forms two
large condensations, one dorsal to the axial mesenchymal column and one
ventral to it (Fig 11-7).
2. The cells of the condensations differentiate into myoblasts (muscle cell
precursors).
3. The dorsal muscle mass gives rise to the extensors and supinators of the
UPPER limb and to the extensors and abductors of the LOWER limb.
4. The ventral muscle mass gives rise to the flexors and pronators of the
UPPER limb and to the flexors and adductors of the LOWER limb. Note:
Some muscles migrate from their site of origin and acquire different functions.
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H. Rotation of the limbs (Fig. 11-10).
1. The upper limbs.
a) They appear in week 4 as small bulges oriented in a coronal plane.
b) They undergo a horizontal flexion in week 6 so that they are now oriented
in a parasagittal plane.
c) They rotate laterally 90 degrees during weeks 6 to 8 so that the elbow
points posteriorly, the extensor compartment lies posterior, and the flexor
compartment lies anterior.
d) The 90 degree lateral rotation of the upper limb bud causes the originally
straight segmental pattern of innervation to twist into a spiral in the adult.
2. The Lower limbs.
a) They ppear in week 4 (about 4 days after the upper limb bud) as small
bulges oriented in a coronal plane.
b) They undergo horizontal flexion in week 6 so that they are now oriented in
a parasagittal plane.
c) They rotate medially 90 degrees during weeks 6 to 8 so that the knee
points anteriorly, the extensor compartment lies anteriorly, and the flexor
compartment lies posterior.
d) The rotation causes the originally straight segmental pattern of innervation to
become twisted in a spiral in the adult.
3. Final anatomic situation of the limbs.
a) Note that the upper limbs rotate laterally 90 degrees, whereas the lower
limbs rotate medially 90 degrees. This sets up the following anatomic
situations:
b) Flexior compartment of the upper limb is anterior, whereas the flexor
compartment of the lower limb is posterior.
c) Extensor compartment of the upper limb is posterior, whereas the extensor
compartment of the lower limb is anterior.
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V. Clinical Applications.
A. Congenital Anomalies of the limbs (Table 11-2).
1. Reduction defects:
a) meromelia!part of a limb is missing (Fig 11-11A).
b) Amelia!an entire limb is missing (Fig 11-11B).
c) Ectrodactyly!
!Absense of any number of fingers or toes.
d) Adactyly!Absense of all the digits on a limb.
2. Duplication defects: supernumerary limb elements.
a) Polydactyly!extra digits (Fig 11-11C).
3. Dysplasia!malformation of the limbs:
a) Syndactyly!fusion of digits (Fig 11-12 & 11-14).
b) Gigantism (Acrodolichomelia)!
!excessive growth of parts of the limb.
c) Phocomelia!
!Short, ill-formed upper or lower limbs.
d) Hemimelia!
!Stunting of distal limb segments.
B. General causes of limb defects.
1. Arrest of development
2. Failure of differentiation
3. Duplication
4. Overgrowth
5. Hypoplasia
6. Focal Defects
7. General skeletal abnormalities that indirectly effect limb development.
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C. Etiology of limb defects. Genetic or teratogenic (Environmental)? Note: Most
human limb defects appear to have a mulifactorial etiology, arising from an
interaction between environmental factors and the individual's genetic makeup.
However, some limbs defects have been attributed to a genetic or an environmental
basis.
1. Genetic basis.
a) Familial associations indicate a genetic basis for some limb anomalies. Both
polydactyly and ectrodactyly often run in families.
b) These defects show an autosomal dominant, autosomal recessive, or Xlinked pattern of inheritiance
c) Other limb defects known to be transmitted as autosomal dominant traits
include partial tibia defect, general micromelia, triphalangeal thumbs, lobster
claw hand and foot (Fig 11-13), and the Adams-Oliver syndrome
(characterized by limb anomalies and defects of the scalp and skull).
d) An autosomal recessive disease characterized by the fusion of the digits
(syndactyly), results from a mutation of the HOX gene HOXD13 (Fig 1114).Note: Four clusters of Hox genes are expressed in vertebrates.
Members of the most 5' members of the HoxD and Hoxa clusters (Hoxd9-13)
are expressed in a distal to proximal transcriptional cascade within the
growing limb bud (Fig 11-21 & Fig 11-22).
e) Chromosomal anomalies!Trisomy 18 causes limb defects.
2. Environmental teratogens. A variety of drugs, metabolic poisons, and other
environmental teratogens have been shown to cause limb defects humans.
a) Agents that influence general cell metabolism or cell proliferation (if
taken during the period of limb morphogenesis).
(1) 5'-fluoro-2-deoxyuridine (an inhibitor of thymidylate synthetase).
(2) Acetazolamide (a carbonic anhydrase inhibitor)
(3) Triethylene melamine (an alkylating agent)
(4) Cadmium (zinc metalloenzyme inhibitor)
b) Febrific (Fever-causing) diseases.Hyperthermia is also a significant cause
of limb defects. Increases in body temperature of only 1 to 2.5C can induce
limb malformations.
c) Therapeutic drugs that have teratogenic effects.
(1) Aspirin.
(2) Dimethadione (Anticonvulsant)
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(3) Retinoic Acid
(4) Thalidomide (spasmolytic and anticonvulsant under the trade name
Contergan). It exerts its effects only when taken during the sensitive
period of limb morphogenesis, between about 4 and 8 weeks.
Thalidomide is thought to disrupt cell adhesion in the limb by
downregulating cell surface adhesion receptors (integrins and selectin)
or by inhibiting angiogenesis. Recently, thalidomide has been utilized
in the treatment of autoimmune and inflammatory conditions.Note: The
incidence of amelia, phocomelia, hypoplasia, syndactyly (Fig 11-16) and
other embryopathies (anotia and cardiac defects) exactly paralleled the
West German sales of Thalidomide, with a lag of about 7 to 8 months (Fig
11-15). About 40% of the thalidomide babies died soon after birth.
d) Amniotic bands (Amniotic band syndrome), oligohydramnios
(insufficient amniotic fluid), and local vascular disruption.
(1) Amniotic Band Syndrome. Occasionally, a band of tissue detaches
from the amnion and wraps around part of the embryo, constricting its
growth and causing malformations. Amniotic bands may amputate or
constrict a developing limb or may induce facial dysplasia by entangling
the head and face (Fig 11-17).
(2) Constricted Uterine environment (and subsequent compressioninduced vascular disruption) cause limb reduction anomalies.
(a) Oligohydramnios!
!insufficient amniotic fluid.
(b) Bicornuate Uterus!a Y-shaped uterus resulting from incomplete
fusion of the paramesonephric ducts during formation of the
uterovaginal canal.
(c) Large benign tumors of the uterine myometrium
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Heart Development
I. Formation and Folding of the Primitive Heart.
A. Lateral endocardial tubes fuse to form the primary heart tube.
1. Cardiogenic region: a horseshoe-shaped zone of splanchnopleuric mesoderm
located cranial and lateral to the neural plate on the embryonic disc (Fig 7.1A).
2. Vasculogenesis: Late in the third week, the cephalic and lateral folding of the
embryo brings the two lateral endocardial tubes into the thoracic region.
Eventually, they meet at the midline and fuse to form a single tube (Fig 7-2).
Note: The fusion of the two tubes is facilitated by programmed cell death in their
contacting surfaces.
B. Formation of the paired dorsal aortae of the primitive circulatory system.
1. The major vessels of the embryo develop at the same time as the endocardial
tubes.
2. The inflow and outflow tracts of the future heart make connections with the
paired lateral endocardial tubes even before these tubes are translocated into the
thorax and fuse to form the heart (Fig 7-1 and Fig 7-3).
3. Outflow tract:
a. The paired dorsal aortae forms the primary outflow tract of the heart. As the
flexion and growth of the cephalic fold carries the endocardial tubes first into
the cervical and then into the thoracic region, the cranial ends of the dorsal
aortae are pulled ventrally until they form a dorsoventral loop (the first aortic
arch) (Fig 7-3D).
b. During the fourth and fifth weeks four more aortic arches will develop in
connection with the pharyngeal arches (Fig 7-5).
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4. Infow tract:
a. The infow to the heart is initially supplied by six vessels, three on each side
(Fig 7-5).
b. Venous blood from the body of the embryo enters the heart through the
common cardinal veins. They are formed by the fusion of the posterior
cardinal veins (drains the trunk) and the anterior cardinal veins (drains the
head region) (Fig 7-5).
c. The vitelline veins drain the yolk sac (Fig 7-5).
d. The umbilical veins deliver oxygenated blood from the placenta to the heart
(Fig 7-5).
C. Subdivsion of the primary heart tube (Fig 7-6).
1. Early in the fourth week (by day 21) sulci and expansions appear in the
presumptive heart tube (Fig 7-6). During the next 5 weeks, these expansions
contribute to various heart chanbers.
2. Starting from the inflow end (inferior) working towards the outflow end
(superior):
a) Sinus Venous: consists of the partially confluent left and right sinus horns
into which the common cardinal veins drain.
b) Primitive atrium: gives rise to parts of both atria.
c) Atrioventricular sulcus: separates primitive atrium and ventricle chambers.
d) Ventricle: gives rise to most of the definitive left ventricle.
e) Bulboventricluar or interventricular sulcus: separtes the ventricle and
bulbus cordis expansions.
f) Inferior bulbus cordis: forms most of the right ventricle.
g) Superior bulbus cordis or conotruncus: forms the distal outflow regions
of the left and right ventricles, including the conus cordis and the truncus
arteriosus.
h) Truncus Arteriosus eventually splits to form the ascending aorta and the
pulmonary trunk. Its superior end is connected to the aortic sac.
i) The aortic sac is continuous with the first aortic arch and, eventually, with
the other four aortic arches.
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D. The four layers of the wall of the primary heart tube (Fig 7-7).
1. Initially the primary heart tube consists of endothelium, but by day 22 the
splanchnopleuric mesoderm invests the fused endocardial tubes and
differentiates into two new layers (2 & 3 below).
2. Myocardium (heart muscle)
3. Cardiac Jelly: a thick matrix that is secreted by the developing myocardium.
Thus it separates the myocardium from the fused endocardial tubes.
4. The serous epicardium (visceral percardium) is formed by a population of
mesothelial cells that are independently derived from splanchnopleuric
mesoderm.
E. Development of the transverse pericardial sinus (Fig 7-8).
1. The primary heart tube is initially suspended in the primitive pericardial cavity by
a dorsal mesocardium (dorsal mesentery of the heart formed of foregut
splanchnopleuric mesoderm).
2. Early in the 4th week the dorsal mesocardium ruptures. The region of the
ruptured dorsal mesocardium becomes the transverse pericardial sinus.
F. Heart tube folding and looping (Fig 7-9).
1. The process of folding and looping establishes the spatial relationships of the
future heart chambers (begins on day 23 and is complete by day 28). Thus,
the result of looping is to bring the four presumptive chambers of the future heart
into their correct spacial relation to each other.
2. The bulbus cordis is displaced inferiorly, ventrally, and to the right.
3. The ventricle is displaced to the left.
4. The primitive atrium is displaced posteriorly and superiorly.
Note: Heart looping is a hot topic in basic heart research, but the mechanism is still
poorly understood. Cultured hearts loop correctly even in the absence of the
primitive pericardium, cardiac jelly, and blood flow.
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II. Remodeling of the primitive vasculature.
A. Shift of venous inflow to the right (no longer bilaterally symetrical).
1. At day 22, the heart and primitive circulatory system are bilaterally symmetrical.
2. The heart starts to beat on day 22, and by day 24 blood begins to circulate
throughout the embryo. At this point, venous return occurs bilaterally from the
right and left sinus horns (Fig 7-10A).
3. In the next few weeks the venous system is remodeled so that all the systemic
venous blood enters the right sinus horn via the superior and inferior venae
cavae (Fig 7-10B, C).
4. During this shift the left sinus horn ceases to grow and eventually gives rise to
the coronary sinus (drains blood from the coronary circulation of the heart
muscle) and the small oblique vein of the left atrium (Fig 10C).
III. Extensive remodeling of the left and right atria.
A. The right sinus horn is incorporated into the right posterior wall of the primitive
atrium (remodeling of the right atrium).
1. As the right sinus horn and the venea cavae enlarge the right side of the sinus
venosus is gradually incorporated into the right posterior wall of the developing
atrium (occurs during the 5th week), giving rise to the sinus venarum (smooth
wall)(Fig 7-11). The sinus venarum eventually gives rise to the definitive right
atrium.
2. The original right half of the primitive atrial wall is displaced ventrally and to the
right eventually giving rise to the right auricle (rough, comblike, trabeculated
surface).
3. The process of intussuseption of the right sinus venosus pulls the ostia
(openings) of the superior and inferior venae cavae and future coronary sinus
into the posterior wall of the definitive right atrium. They eventually form the
orifices of the superior and inferior venae cavae and the orifice of the
coronary sinus (Fig 7-12).
4. The left venous valve (eventually becomes part of the septum secundium
involved in the septation of the definative right and left atria) and right venous
valves (eventually forms the valve of the inferiror vena cava and the coronary
sinus) then form on either side of the three ostia (Fig 7-12).
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B. The trunk of the pulmonary venous system is incorporated into the posterior wall of
the left atrium (Remodeling of the left atrium).
1. Early in the 4th week a single pulmonary vein sprouts from the left side of the
primitive atrium and then branches twice to produce two right and left
pulmonary veins (Fig 7-11). These veins anastomose with veins in the
developing bronchial buds.
2. The process of intussuseption, during the 5th week, incorporates the trunk and
first two branchings of the pulmonary vein system into the posterior wall of the
left side of the primitive atrium (Fig 7-11 and Fig 7-12). They form the smooth
wall of the definitive left atrium.
3. Thus, the pulmonary venous system opens into the atrium initially through a
single large orifice, then transiently through two orifices, and finally through the
four orifices of the definitive pulmonary veins (Fig 7-13).
IV. Septation of the atria and division of the atrioventricular canal.
A. Septum primum formation.
1. Day 26, a crescent shaped wedge of tissue called the septum primum begins to
extend into the atrium (Fig 7-14).
2. During the 5th week, the free edge of the septum primum grows caudally toward
the atrioventricular canal.
3. The ostium primum, a foramen, is diminishing.
Note: The fetal heart chambers and outflow tracts contain foramenina and ducts
that shunt the oxygenated blood entering the right atrium to the left ventricle and
aortic arch, thus largely bypassing the pulmonary circulation. These shunts close at
birth, abruptly separating the two circulation systems (example: Ductus
Arteriosus!a connection between the pulmonary artery and aorta. When it closes
it forms the ligamentum arteriosum. A Patent Ductus Arteriosus occurs when
this shunt does not close. It is very common in premature infants and maternal
rubella infection. Prostaglandin synthesis inhibitors can be used to promote
closure).
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B. Septum primum and septum intermedium fusion.
1. The left, right, superior, and inferior endocardial cushions begin to form
around the periphery of the atrioventricular canal.
2. Late 6th week, the superior and inferior cushions meet and fuse, forming the
septum intermedium. This divides the common atrioventricular canal into right
and left atrioventricular canals (Fig 7-15A, 7-16, and 7-17C).
3. End of the 6th week, the growing edge of the septum primum fuses with the
septum intermedium (Fig 7-15A and Fig 7-19D).
4. Fusion destroys the ostium primum. Programmed cell death near the superior
edge of the septum primum creates a hole, forming a new foramen, the ostium
secundum. Thus, a new channel for right-to-left shunting opens before the old
one closes.
C. An incomplete septum secundum forms next to the septum primum.
1. A second crescent shaped ridge of tissue (the septum secundum) appears on
the ceiling of the right atrium adjacent to the septum primum (Fig 7-15).
2. The foramen ovale is formed near the floor of the right atrium (Fig 7-16).
3. Throughout fetal life, blood shunts from the right atrium to the left atrium passing
through the foramen ovale and ostium (foramen) secundum.
Note: Dilation of pulmonary vasculature and cessation of umbilical flow reverses the
pressure difference, pushing the flexible septum primum against the more rigid
septum secundium. This closes the shunt a birth.
V. Realignment of the heart (Fig 7-17).
A. The atrioventricular canal is repositioned to the right.
1. During the 5th week, the right side of the canal comes into alignment with the
future right atrium and right ventricle.
2. At the same time, the canal is being divided into right and left canals by the
growth of the superior and inferior endocardial cushions.
3. The new alignment simultaneously provides the left ventricle with a direct outflow
path through the conus cordis to the truncus arteriosus.
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VI. Formation of the atrioventricular valves and septation of the ventricles and
outflow tracts.
A. Septation of the ventricles (Fig 7-18 & 7-19).
1. End of the 4th week, the muscular ventricular septum begins to grow towards the
septum intermedium, but halts in the middle of the 7th week before they touch.
Note: If fusion occurred to soon, the left ventricle would be shut off from the
ventricular outflow tract.
2. Myocardium begins to thicken and myocardial ridges or trabeculae appear on
the inner wall of both ventricles.
3. On the right wall of the muscular ventricular septum the moderator band
(prominent trabeculation) has formed. This region connects the muscular
septum with the anterior papillary muscle (forms part of the right
atrioventricular valve) (Fig 7-18B & Fig 7-19).
B. Atrioventricular valve formation (Fig 7-19).
1. 5th-8th weeks, atrioventricular valves form.
2. Anterior and posterior cusps (leaflets) form on either side of the both canals (Fig
7-19D).
3. The free edge of each leaflet is attached to the venticular walls by the chordae
tendinae which insert into the papillary muscles of the myocardium (Fig19C,D).
Note: The valve leaflets are designed so that they fold back to allow blood to enter
the ventricles from the atria during diastole but shut to prevent backflow when the
ventricles contract (systole).
4. During the third month the right atrioventricular valve (tricuspid valve) usually
develops a third small septal cusp. The left atrioventricular valve (bicuspid
valve) has only anterior and posterior leaflets (Fig 7-19D).
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C. Septation of the cardiac outflow tract and final septation of the ventricles (Fig 7-20).
Note: Further septation of the ventricles and the outflow tract must occur in tight
coordination to produce a functional heart. A large proportion of cardiac defects are
due to errors during the septation process.
1. Beginning of the 5th week, the right and left truncoconal swellings (truncoconal
septae) grow out from the walls of the common ventricular outflow tract at the
junction of the truncus arteriosus and conus cordis (Fig 7-20A,B).
2. When they meet , they begin to fuse together superiorly and inferiorly ( the
growing membranous ventricular septum), separating the right (eventually the
pulmonary trunk) and left (eventually the ascending aorta) ventricular outflow
pathways. Septation is complete when the truncoconal swellings fuse with the
inferior endocardial cushion and the muscular interventricular septum, thus
separating the right and left ventricles.
Note: Failure of complete fusion, resulting in a ventricular septal defect
(membranous), is the most common congenital heart defect.
3. The growing truncoconal septae apparently arise in a spiral along the walls of the
truncus arteriosus and the ventricular outflow tracts. As a result, the left and right
ventricular outflow tracts (eventually the aorta and pulmonary trunk) twist around
each other in a helical arrangement (Fig 7-20).
4. Truncus swelling also contribute to the semilunar valves in the aortic and
pulmonary trunks via the initial formation and splitting of tubercles (Fig 7-21).
The tubercles give rise to the cusps of the three-cusped semilunar valves that
prevent backflow from the aorta and pulmonary trunk into the ventricles.
D. Neural crest contribution to the truncoconal septum (Fig 7-29).
1. The critical components of the truncoconal septum are derived from the cardiac
neural crest.
2. Cardiac neural crest invade the truncoconal swellings after migrating through the
pharyngeal arches 3, 4, and 6.
3. Cardiac neural crest cells give rise to:
a. connective and smooth muscle of the truncoconal septa.
b. Cardiac ganglia
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4. Cardiac neural crest ablation revealed the role of neural crest in normal and
aberrant septation of the cardiac outflow tracts. If the cardiac neural crest is
removed before it begins to migrate, the truncoconal septa completely fail to
develop, and blood leaves both ventricles through a persistent truncus
arteriosus.
5. Other anomalies after cardiac neural crest ablation include:
a. dextroposed aorta
b. ventricular septal defects
c. tetralogy of Fallot
6. Also the pathways that cardiac neural crest cells migrate through are very
important. For example, the CHARGE and DiGeorge syndromes (which have
cardiac anomalies) result from defects of the pharyngeal arches.
VII.
Clinical applications of Congenital Cardiovascular Disease.
A. Stats on cardiovascular malformations.
1. Cardiovascular malformations are the most common type of life-threatening
congenital defect.
2. Congenital cardiovascular malformations account for about 20% of all congenital
defects observed in live-born infants (8 of every 1,000 live births).
3. Ventricular septal defects (membranous) are the most common congenital
cardiovascular malformation.
B. Cause of cardiovascular malformations.
1. Neither the cause nor the pathogenesis of most heart defects is understood. A
few can be associated with specific genetic errors or environmental teratogens,
but the etiology of most malformations appear to be multifactorial.
2. Single-gene mutations causing cardiac malformations:
a. Familial hypertrophic cardiomyopathy (FHC): gradual thickening of the
ventricular walls and interventricular septum, disorganization of the muscle
fibrils, and formation of loose connective tissue. These defects can cause
arrhythmias and pumping inefficiency, leading to cardiac failure and sudden
death in early adulthood. (mutation of the beta-cardiac myosin heavy
chain gene)
b. Congenital long QT syndrome: causes cardiac arrhythmias (repolarization
of the ventricle--resting EKG is abnormal), leading to fainting and sudden
death (mutation in one of the cardiac ion channels).
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3. Perturbation of any normal process of heart development may result in
malformation.
a. Acardia (Fig 7-22): Error in primitive heart tube formation.
b. Dextrocardia (Fig 7-23): The primative heart tube folds to the right instead
of to the left. Most individuals with Dextrocardia exhibit situs inversus.
c. Atrial Septal (Septum Secundum) Defect (Fig 7-24): The septum
secundum is too short to cover the ostium secundum completely. Thus when
the septum primum and septum secundum are pressed together at birth the
atrial septae persists, causing a continued mixing of right and left atrial blood
after birth. Infants with this abnormality are generally asymptomatic, but the
persistent increase in flow to the right atrium may lead to the enlargement of
the right ventricle and pulmonary trunk. Cardiac failure may ensue later in
life. This is a common malformation of trisomy 21.
d. Atrioventricular Septal Defect (endocardial cushion defect): Arises from
failure of the superior and inferior endocardial cushions to fuse. Most
common cardiac malformation in Down Syndrome. It results in persistent
left-to-right shunting of blood after birth. In severe cases congestive heart
failure may occur.
e. Double-outlet left ventricle malformation: The aortic and pulmonary
outflow tracts both connect to the left ventricle. The right ventricle becomes
hypoplastic because it has no outflow tract.
f. Ventricular Septal Defects: The most common of all congenital heart
malformations. This defect can arise from several causes. One example, is
the failure of the muscular and membranous ventricular septa to fuse.
Membranous is the most common type.
g. Tricuspid and mitral valve defects: Valve Atresia is the complete loss of
the valve orifice. Ebstein’s disease (tricuspid valve anomaly) causes a
displaced valve and abnormal shaped leaflets. The dysfunctional valve
allows blood to regurgitate into the right atrium and also blocks access to the
pulmonary trunk. This causes cyanosis (in adequate oxygenated blood)
and an enlarged left ventricle in the newborn.
h. Persistent Truncus Arteriosus (Fig 7-26A): because of abnormal neural
crest the truncoconal septa do not form at all, resulting in blood that mixes
from both sides of the heart in the common outflow tract (ventricular septal
defect also occurs). Thus both the body and the lungs receive partially
deoxygenated blood. Untreated infants usually die within the first 2
years. Surgical correction is very difficult (75% mortality).
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i.
Transposition of the great vessels (Fig 7-26B,C): The truncoconal septa
develop but do not display the usual spiral pattern. This results in a left
ventricle that empties into the pulmonary circulation and a right ventricle that
empties into the systemic circulation. This defect is the leading cause of
death in infants under 1 year old with cyanotic heart disease. Why is this
condition not immediately fatal?
j.
Tetralogy of Fallot (Fig 7-27): Represents a group of cardiac
malformations that arise through a pathogenetic cascade (a primary
malformation sets off a cascade of effects that lead to other malformations).
The four classic malformations in this syndrome are pulmonary stenosis,
ventricular septal defect, overriding aorta, and right ventricular
hypertrophy. The primary defect is a malalignment of the muscular outlet
septum between the subpulmonary and subaortic outlets.
k. Hypoplastic left heart: Occurs when the normal shunting of blood from the
right to the left atrium during gestation is restricted. The left side of the heart
becomes underdeveloped. This syndrome has a multifactorial etiology, but it
can be associated with the genetic disease phenylketonuria.
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Gastrointestinal Tract Development
Body Cavities / Foregut
I. Embryonic folding of the trilaminar germ disc.
A. Foregut, midgut, and hindgut formation.
1. The foregut, midgut, and hindgut of the primitive gut tube are formed by the
combined action of differential growth and lateral and cephalocaudal folding
(during the 3rd and 4th weeks) (Fig 3-6 , Fig 4-1, Fig 6-1, Fig 9-1, Fig 9-10).
2. As folding occurs, the embryo grows faster than the yolk sac, converting the flat
trilaminar germ disc into an elongated cylinder.
3. The cylinder consists of three concentric nested tubes: Ectoderm (outer layer),
Endoderm (central layer, primary gut tube), and Mesoderm (separates
ectoderm and endoderm and contains the coelom) (Fig 6-1& Fig 4-1). Thus, the
three germ layers retain the same topological relation to each other.
4. Fusion of the ectoderm, mesoderm, and endoderm from opposite sides is
prevented in the immediate vicinity of the vitelline duct but not in more cranial
and caudal regions.
B. Arterial supply distinguishes the foregut, midgut, and hindgut.
1. The gut tube initially consists of cranial and caudal blind-ending tubes, the
presumptive foregut (terminates in the buccopharyngeal membrane) and
hindgut, (terminates in the cloacal membrane) and a central midgut, which still
opens ventrally to the yolk sac (Fig 9-1).
2. The neck of the yolk sac narrows and becomes the vitelline duct. The vitelline
duct and yolk sac are eventually incorporated in the umbilical cord.
3. The gut tube and its derivatives are vascularized by the unpaired ventral
branches of the descending aorta (Fig 8-5).
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4. Fourth week, vitelline arteries emerge from the ventral surfaces of the dorsal
aortae to supply the yolk sac. By the end of the fourth week many of the
vitelline channels disappear, leaving five in the thoracic region (supplies the
thoracic part of the foregut--the pharynx and thoracic esophagus) and three
(the celiac, superior mesenteric, and inferior mesenteric arteries) in the
abdominal region (Fig 8-5).
5. Celiac trunk artery: supplies the abdominal foregut--the abdominal
esophagus, stomach, and superior half of the duodenum and its derivatives.
6. Superior mesenteric trunk artery: supplies the midgut.
7. Inferior mesenteric artery: supplies the hindgut.
C. The primitive abdominal gut is suspended by the dorsal mesentery.
1. By the end of the fourth week, the portion of the gut tube within the peritoneal
cavity (the abdominal esophagus to the superior end of the developing cloaca)
hangs suspended by the dorsal mesentery (Fig 9-2).
2. In the stomach region the gut tube remains connected to the ventral body wall by
the thick septum transversum. By the fifth week, the caudal portion of the
septum transversum thins to form the ventral mesentery (connects stomach and
liver to the ventral body wall) (Fig 9-2).
3. Septum transversum: on day 22 it appears as a thickened bar of mesoderm
lying between the cardiogenic area and the cranial margin of the embryonic disc
(Fig 6-1, Fig 6-5, & 9-2). Cephalic folding wedges the mesoderm between the
cardiogenic region and the neck of the yolk sac (Fig 6-1). Thus, it forms a
ventral partition separating the intraembryonic coelomic cavity into a primitive
pericardial cavity superiorly and a peritoneal cavity inferiorly (Fig 6-5). These
two cavities remain in continuity through the posterior pericardioperitoneal
canals. The septum transversum eventually gives rise to part of the diaphragm
and the ventral mesentery of the stomach and duodunum.
4. Early 5th week to the 7th week, a pair of transverse membranes, the
pleuroperitoneal membranes (gives rise to the posterior region of the
diaphragm) grow from the posterior body wall to meet the posterior edge of the
septum transversum. This closes the pericardioperitoneal canals (Fig 6-7 A,B).
Note: The left pericardioperitoneal canal is larger than the right and closes later.
This difference may account for the fact that congenital diaphragmatic hernias of
the abdominal viscera are more common on the left side than on the right.
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II. The abdominal foregut development.
A. The abdominal foregut gives rise to the stomach, duodenum, liver, pancreas,
and gall bladder.
B. The stomach rotates as it develops.
1. Early 4th week, the stomach becomes apparent as the foregut inferior to the
septum transversum expands slightly (Fig 9-3). The thoracic foregut also begins
to elongate (days 26-28).
2. 5th week, the dorsal wall of the stomach grows faster than the ventral wall,
forming the greater curvature of the stomach and the lesser curvature of the
stomach.
3. 7th week, the fundus and cardiac incisure results from the continued differential
expansion of the superior part of the greater curvature.
4. 7th and 8th weeks, the stomach (and the dorsal/ventral mesentery & the
left/right vagal branches) rotates 90 degrees around the craniocaudal axis so
that the greater curvature lies to the left and the lesser curvature lies to the right
(Fig 9-3D). The stomach also rotates slightly around a ventrodorsal axis so
that the greater curvature faces slightly caudally and the lesser curvature slightly
cranially.
5. The differential thinning of the right side of the dorsal mesogastrium (the portion
of the dorsal mesentery attached to the stomach) is also believed to play a role in
the rotation process.
C. Formation of the lesser/ greater sac and the greater omentum of the peritoneal
cavity (Fig 9-5).
1. When the duodenum swings to the right, it fuses to the dorsal body wall,
enclosing the space (the lesser sac) posterior to the stomach and within the
expanding cavity of the greater omentum . The rest of the peritoneal cavity is
called the greater sac. The principal passageway between the greater and
lesser sacs is the epiploic foramen of Winslow. It is the repositioning of the
stomach, liver, and lesser omentum (mentioned later) that forms this narrow
canal.
2. The rotation of the stomach and growth of the dorsal mesogastrium creates the
greater omentum that dangles from the greater curvature of the stomach
(drapes over more inferior organs of the abdominal cavity).
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3. The upper recess of the lesser sac is the portion of the lesser sac directly
dorsal to the stomach. The cavity within the greater omentum is called the lower
recess of the lesser sac. Eventually, during fetal life, the anterior and posterior
folds of the greater omentum fuse together obliterating the lower recess.
D. Endodermal buds of the duodenum give rise to the digestive glands (Fig 9-6).
1. Day 22, the hepatic plate, a small endodermal thickening, appears on the
ventral side of the duodenum.
2. The next few days, the hepatic plate proliferates and forms the hepatic
diverticulum (gives rise to the ramifying liver cords (hepatocytes) to the bile
canaliculi and hepatic ducts), which grows into the inferior region of the septum
transversum.
3. The mesoblastic supporting stroma of the liver develops from splanchnopleuric
mesoderm originating near the cardiac region of the stomach.
4. The liver is a major early hematopoietic organ of the embryo.
5. Day 26, the cystic diverticulum (gives rise to the gallbladder and cystic duct)
forms first as a endodermal thickening on the ventral side of the duodenum at the
base of the hepatic diverticulum. It eventually buds into the ventral mesentery.
6. The common bile duct forms at the junction of the hepatic and cystic ducts.
Note: The gallbladder and cystic duct develop from histologically distinct
populations of duodenal cells.
7. Also on day 26, the dorsal pancreatic bud (eventually gives rise to the head,
body, and tail of the pancreas) forms opposite of the hepatic diverticulum and
grows into the dorsal mesentery. As it elongates, the ventral pancreatic bud
(eventually connected to the common bile duct and gives rise to the uncinate
process) sprouts into the ventral mesentery just caudal to the developing
gallbladder.
8. 5th week, the mouth of the common bile duct and the ventral pancreatic bud
migrate posteriorly around the duodenum to the dorsal mesentery.
Note: An annular pancreas is a condition that arises because the two lobes of
the ventral (a normal variation) pancreatic bud migrate in opposite directions
around the duodenum to fuse with the dorsal pancreatic bud. This compresses
the duodenum and may cause gastrointestinal obstruction (Fig 9-7).
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9. Late 6th week, the two pancreatic buds fuse to form the definitive pancreas
which fuses to the dorsal body wall like the duodenum. The duct from the dorsal
bud to the duodenum usually degenerates (can persist as an accessory
pancreatic duct draining into the minor duodenal papilla), leaving the ventral
pancreatic duct (main pancreatic duct) as the only conduit to the duodenum.
10. The main pancreatic duct and the common bile duct meet and empty into the
duodenum at the major duodenal papilla (ampulla of Vater).
III. Spleen development (a vascular lymphatic organ).
A. Spleen is derived from the dorsal mesogastrium, not from the gut tube
endoderm.
1. Late 4th week, a mesenchymal condensation develops in the dorsal
mesogastrium of the lesser sac.
2. 5th week, the condensation differentiates into the spleen. Accessory spleens
may also develop near the primary spleen.
3. The rotation of the stomach and growth of the dorsal mesogastrium translocate
the spleen to the left side of the abdominal cavity. Also, the rotation of the dorsal
mesogastrium forms the renal splenic ligament between the spleen and the left
kidney. The portion of the dorsal mesentery between the spleen and the
stomach is the gastroplenic ligament.
B. Functions of the spleen.
1. Until the 14 week, the spleen is strictly hematopoietic.
2. 15 to 18 weeks, the transformation stage, the organ develops a lobular
architecture. After this stage, the stage of lymphoid colonization begins as Tlymphocyte precursor cells begin to enter the spleen.
3. 23 weeks, B-cell precursors arrive and form the B-cell regions of the definitive
spleen. At this point the spleen has acquired its definitive lymphoid character.
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IV. Formation of the liver and associated membranes.
A. Growing liver bud and developing serosal membranes.
1. As the liver bud (an outgrowth from the ventral surface of the foregut) grows into
the ventral mesentery (caudal region of the septum transversum), its crown
moves toward the developing diaphragm. Eventually, this region of the septum
transversum will give rise to a number of membranous structures, including the
serous (derived from splanchnic mesoderm) coverings of the liver and the
membranes that attach the liver to the stomach and to the ventral body wall
(Table 9-2).
2. 6th week, The enlarging liver makes contact with the superior and inferior
coverings of the septum and begins to split them apart (Fig 9-8).
3. Inferior covering (serosal membrane) of the septum becomes the visceral
peritoneum that covers almost the entire surface of the liver.
4. The superior end of the liver makes direct contact with the developing central
tendon of the diaphragm (which had formed from the superior region of the
septum transversum) and thus has no peritoneal covering (bare area of the
liver) (Fig 9-8).
B. Ligament formation.
1. The coronary ligament subsequently developes as a fold or reflection around
the margin of the bare area. In the bare area where the liver and diaphragm
come in direct contact, the hepatic portal vessels and the systemic veins of
the diaphragm anastomose.
2. The membranous falciform ligament arises from the ventral mesentery that
attaches the liver to the ventral body wall. The free caudal margin of this
membrane carries the umbilical vein from the body wall to the liver.
3. The ventral mesentery between the liver and the stomach thins out to form a
translucent membrane called the lesser omentum.
4. The caudal border (of the lesser omentum) connecting the liver to the duodenum
is called the hepatoduodenal ligament (contains the portal vein, hepatic
arteries, hepatic duct, cystic duct, and common bile duct).
5. The region of the lesser omentum between the liver and the stomach is called
the hepatogastric ligament.
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Gastrointestinal Tract Development
Midgut / Hindgut
V. Rotations of the midgut and subsequent reconfiguration of the small and large
intestine.
A. Ileum elongation.
1. 5th week, the presumptive ileum (the cecal primordium is at the junction
between the ileum and the colon) begins to elongate rapidly.
2. The ileum grows more rapidly than the abdominal cavity, causing the midgut to
form a dorsoventral hairpin called the primary intestinal loop (Fig 9-9A).
3. The cranial limb of the loop will give rise to most of the ileum.
4. The caudal limb of the loop will give rise to the ascending and transverse
colons.
5. The apex of the primary intestinal loop is attached to the umbilicus by the
vitelline duct.
6. The superior mesenteric artery runs down the long axis of the loop.
7. Early 6th week, due to pressure from the growing liver and elongating midgut the
primary intestinal loop herniates into the umbilicus (Fig 9-9B).
B. 90-degree counterclockwise rotation of the primary intestinal loop.
1. During the herniation process the primary intestinal loop rotates around the axis
of the superior mesenteric artery (dorsoventral axis).
2. As viewed from the front, it rotates 90-degrees counterclockwise. Thus, the
cranial limb moves caudally and to the embryo’s right, while the caudal limb
moves cranially and to the embryo’s left (Fig 9-9B).
3. 8th week, the first rotation is complete. At the same time the lengthening
jejunum and ileum (midgut) develop into a series of folds called the jejunal-ileal
loops. The expanding cecum sprouts a vermiform appendix (wormlike) (Fig 99C).
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C. Retraction and additional rotation of the midgut.
1. The retraction of the midgut into the abdominal cavity is poorly understood.
2. As the intestinal loop re-enters the abdomen it rotates an additional 180
degrees counterclockwise. Thus the retracting colon has rotated a total of
270 degrees relative to the posterior wall of the abdominal cavity (Fig 9-9C-E).
3. 11th week, rotation and retraction are complete. The cecum is now in a position
just inferior to the liver. Between the 73rd and 77th days, the cecum is displaced
inferiorly, pulling down the proximal hindgut to form the ascending colon
(midgut).
D. The mesenteries shorten and fold, reconfiguring the midgut (Fig 9-10).
1. The dorsal mesenteries of the ascending colon and descending colon
shorten and fold. This bings the these organs into contact with the dorsal body
wall, where they adhere and become secondarily retroperitoneal.
a. Intraperitoneal viscera!
! the abdominal gut tube and its derivatives that are
suspended (from dorsal mesentery) in what will later become the peritoneal
cavity (Fig 6-4).
b. Retroperitoneal viscera!
! organs that are not suspended by mesentery. It
means that an organ is located behind the peritoneum from a viewpoint inside
the peritoneal cavity. Thus the kidneys and bladder are an example of
retroperitoneal (Fig 6-4).
c. Secondarily retroperitoneal!
! some parts of the gut tube that are initially
suspended by mesentery later become fused to the body wall, thus taking on
the appearance of retroperitoneal organs. Examples of secondarily
retroperitoneal are the ascending and descending colon, the duodenum, and
the pancreas (Fig 6-4).
2. The transverse colon does not become fixed to the body wall but remains an
intraperitoneal organ suspended by mesentery.
3. The sigmoid colon (the most inferior portion of the colon) also remains
suspended by mesentery.
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VI. The distal hindgut gives rise to the rectum and the urogenital sinus (Fig 9-11).
A. Partition of the cloaca.
1. The part of the primitive gut tube lying beneath the cloacal membrane forms an
expansion called the cloaca.
2. 4th-6th weeks, the cloaca is partitioned into a posterior rectum and an anterior
primitive urogenital sinus (gives rise to the bladder, the pelvic urethra, and
urogenital sinus) by the growth of the coronal partition called the urorectal
septum (Fig 9-11).
3. The distal edge of the urorectal septum fuses with the cloacal membrane.
This divides the membrane into an anterior urogenital membrane and a
posterior anal membrane.
4. The zone of fusion between the urorectal septum and the cloacal membrane
becomes the perineum.
B. The two intergrated mesodermal septal systems of the urorectal septum.
1. Recent evidence suggests that the urorectal septum is formed by the intergration
of the Tourneux fold and a pair of lateral folds called the Rathke folds (Fig 911).
2. 4th week, the Tourneux fold, a crescentic wedge of mesoderm, grows inferiorly
between the allantois and the cranial end of the cloaca. It ceases to grow when it
reaches the level of the future pelvic urethra. The Rathke folds (mesoderm)
arise from either side of the cloacal cavity and grow toward the midline. The
Rathke folds then fuse with each other and the Tourneux fold to complete the
urorectal septum (Fig 9-11).
C. Anorectal canal formation (Fig 9-12).
1. The superior two-thirds of the anorectal canal forms from the distal part of the
hindgut.
2. The inferior one-third of the anorectal canal is derived from an ectodermal pit
(anal pit or proctodeum).
3. In the adult, the border between the superior end of the anal pit and the inferior
end of the rectum is demarcated by the mucosal folds (pectinate line).
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4. The vasculature of the anorectal canal is consistent with this dual origin.
Branches of the inferior mesenteric arteries and veins that serve the hindgut also
supply the region superior to the pectinate line. The region inferior to the
pectinate line, however, is supplied by the branches of the internal iliac arteries
and veins.
Note: The tributaries of the superior rectal vein and the tributaries of the inferior
rectal vein anastomose within the mucosa of the anorectal canal. If the blood
flow into the inferior vena cava is blocked it may cause this region to swell into
hemorrhoids.
D. Digestive tube recanalization.
1. 6th week, the endodermal epithelium of the gut tube proliferates until it
completely ocludes the gut tube lumen (Fig 9-13).
2. 7th & 8th weeks, the gut tube is recanalized by the formation of vacuoles that
eventually coalesce.
3. 9th week, the endodermal lining of the new gut differentiates into the definitive
mucosal epithelium.
Note: Stenosis or duplication of the digestive tract may result from incomplete
recanalization (Fig 9-13).
VII.
Clinical applications—anomalies of gastrointestinal development.
A. Anterior abdominal wall defects.
1. Omphalocele!
! organs protrude from the anterior abdominal wall due to the
failure of the umbilicus to close completely (2.5 of 10,000 births).
a. In some individuals, the herniation of the midgut in the 6th week occurs
normally, but the organs do not retract properly in the 10th week (organs
protrude into a thin/ruptured amniotic membrane only) (Fig 9-14A).
b. In other individuals, the organs retract properly, but then herniate secondarily
because the ventral abdominal wall fails to close in the region of the umbilicus
(organs protrude into a sac composed of peritoneum, subserous fascia,
and amniotic membrane).
2. Ectopia cordis!
! The abdominal wall defect in an omphalocele is not always
limited to the umbilicus. In this case there is a defect of the abdominal wall
cranial to the umbilicus, causing the heart to eventrate (Fig 9-14B).
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3. Pentalogy of Cantrell!
! sometimes a omphalocele may occur in conjunction
with a variety of cardiac and renal defects. In this case an omphalocele,
diaphragmatic hernia (Which side would this most likely occur?), sternal cleft,
ectopia cordis, and intracardiac anomaly.
4. Gastroschisis!
! a defect of the ventral abdominal wall between the developing
rectus muscles just lateral to the umbilicus (does not involve the umbilicus—it
closes normally) (Fig 9-15). This defect usually occurs on the right side due to
an abnormal involution of the right umbilical vein and the consequent
maldevelopment of the ventral abdomianl wall in that region. Organs rarely
eventrate, but if they do they are not enclosed in an amnioperitoneal sac. This
disorder is also less likely to be associated with other abnormalities (including
chromosomal).
5. Epispadias!
! the left and right halves of the penile tubercle do not fuse
completely. Early in the fifth week, the cloacal folds (pair of swellings) develop
on either side of the cloacal membrane and eventually go on to form the genital
tubercle (Fig 10-18) ). Thus, hindgut structures are exposed through the
defective penile urethra opening.
6. Exstrophy of the bladder!
! the bladder is revealed by an abdominal wall
defect.
7. Exstrophy of the cloaca!
! both the bladder and the anorectal canal are
exposed (Fig 9-16).
Note: #5-7 have abdominal wall defects (secondarily) due to the anomalous
development of the cloacal membrane (either enlarged cloacal membrane or
precocious disruption of the cloacal membrane). These malformations are about
twice as common in males as in females.
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B. Abnormal rotation and fixation of the midgut.
1. Nonrotation of the midgut (left-sided colon)!
! arises when the primary
intestinal loop fails to undergo the normal 180-degree counterclockwise rotation
as it is retracted into the abdominal cavity (Fig 9-17). The cranial limb of the
primary intestinal loop ends up on the right side, while the caudal limb of the
primary intestinal looop (presumptive colon) ends up on the left side. Also, the
secondarily retroperitoneal placement (fusion to dorsal body wall) of the intestine
may not occur.
2. Reversed rotation of the midgut!
! the 180–degree rotation occurs clockwise
instead of counterclockwise, so the net rotation of the midgut is 90 degree
clockwise (Fig 9-18). The duodenum lies ventral to the transverse colon
instead of dorsal to it. The duodenum does not become secondarily
retroperitoneal, but the transverse colon does (it is normally intraperitoneal).
3. Mixed rotations of the midgut (malrotations)!
! mixed or uncoordinated
behavior of the two limbs of the primary intestinal loop. The cephalic limb of the
primary intestinal loop undergoes only the initial 90-degree rotation, whereas the
caudal limb undergoes only the later 180-degree rotation (Fig 9-19). The
duodenum becomes fixed on the right side of the abdominal cavity, and the
cecum becomes fixed near the midline (just inferiror to the pylorus of the
stomach). The abnormal placement of the cecum may cause the duodenum
to be enclosed by a band of thickened peritoneum.
Note: A significant number of intestinal obstruction (or constriction) cases are
caused by abnormal rotation (or fixation) of the midgut. Specific regions of the
intestine can be pinned against the dorsal body wall by bands of abnormal
mesentery. Also, the malrotation may cause the midgut to be suspended from a
single point of attachment on the dorsal body wall. These suspended coils are
prone to volvulus (bilious vomiting is a common symptom) (Fig 9-20). The
intestinal volvulus may also compress part of the intestinal vasculature
(leads to intestinal ischemia or infarction) or lymphatic vessels (leads to
venous mucosal engorgement and consequent gastrointestinal bleeding).
The presence of a rotational abnormality is usually signaled during childhood by
abdominal pain, vomiting, gastrointestinal bleeding, or failure to thrive (some
case are silent until adulthood). These defects can be repaired surgically.
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C. Vitelline duct and allantois defects.
1. Meckel’s diverticulum!
! the vitelline duct normally regresses between the 5th
th
and 8 weeks, but in this disorder it persists as a remnant of variable length and
location (Fig 9-21). Meckel’s diverticulum can manifest any of the followin
conditions:
a. Typical Meckel’s diverticulum!
! a fingerlike projection of the ileum located
about 100cm proximal to the cecum.
b. Omphalomesenteric fistula!
! a patent fistula connects the umbilicus with
the ileum.
c. Omphalomesenteric cyst!
! an isolated cyst suspended by ligaments.
d. Omphalomesenteric ligament!
! a fibrous band connecting the ileum and
anterior body wall at the level of the umbilicus.
Note: Twice as common in males. Individuals with a Meckel’s
diverticulum develop symptoms of intestinal obstruction, gastrointestinal
bleeding, or bowel sepsis. Symptoms may closely mimic appendicitis.
2. Urachal anomalies!
! caused by the incomplete obliteration of the lumen of the
allantois and bladder apex. The urachus or median umbilical ligament is formed
from the allantois and constricted bladder apex. This band runs from the bladder
to the umbilicus (Fig 9-22A). In very rare cases the allantois or bladder apex
remain patent, resulting in a patent urachus, umbilical urachal sinus,
vesicourachal diverticulum, or urachal cyst (Fig 9-22B-E).
Note: The initial symptoms of infection (due to leakage of urine from the
umbilicus, urinary tract infections, and peritonitis) are easily confused with those
of appendicitis.
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Urogenital System Development
Renal System Development
I. Development of Three Nephric Systems.
Note: The intermediate mesoderm (Fig 10-1) gives rise to the nephric structures
of the embryo, to portions of the gonads, and to the male genital duct system. Three
sets of nephric structures (cervical nephrotomes, mesonephroi, and
metanephroi, the definitive kidneys) develop in craniocaudal succession from
the intermediate mesoderm.
A. Cervical nephrotomes.
1. Early 4th week!
! five to seven paired cervical segments of intermediate
mesoderm give rise to a nephric vesicle/nephrotome (small, hollow ball of
epithelium) (Fig 10-2A).
2. Also referred to as the pronephros (Greek for first kidney) because they
resemble the functional embryonic pronephroi of some lower vertebrates.
3. The cervical nephrotomes are transient and nonfunctional. They disappear by
day 24 or 25.
B. Mesonephroi.
1. Early 4th week!
! nephric (mesonephric) tubules develop within a pair of
mesonephroi/mesonephric ridges (elongated swellings of intermediate
mesoderm located on either side of the vertebral column) from the upper thoracic
region to the third lumbar level (Fig 10-2B-D).
2. Also early in the 4th week!
! the mesonephric ducts (intermediate mesoderm
origin) first appear in the form of a pair of solid longitudinal rods (dorsolateral to
the developing mesonephric tubules) (Fig 10-2A & Fig 10-3). These rods grow
caudally into the lower lumbar region guided by an adhesion gradient between
the ectoderm and endoderm.
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3. By day 26, the rods diverge from the intermediate mesoderm and fuse with the
ventrolateral walls of the cloaca (Fig 10-2 & Fig 10-4). The region of fusion
eventually becomes the posterior wall of the future bladder. During the fusion
process the rods also begin to cavitate at their distal ends, forming a lumen.
Cavitation progresses cranially forming the mesonephric ducts.
4. End of 5th week!
! the cranial regions of the mesonephroi undergo regression,
leaving about 20 pairs of tubules occupying the first three lumbar levels.
5. The mesonephric tubules differentiate into excretory units that resemble an
abbreviated version of the adult nephron (Fig 10-2D).
6. The medial end of the tubule forms the Bowman’s capsule (a cup-shaped
sac) which raps around the glomerulus (a knot of capillaries produced on
branches of arteries sprouting from the dorsal aorta), forming the renal
corpuscle.
7. Each renal corpuscle and nephric tubule is called a mesonephric excretory
unit.
8. The lateral tip of each mesonephric tubule fuses with the mesonephric duct,
opening a passage from the excretory units to the cloaca.
9. 6th to 10th weeks!
! the mesonephric excretory units are functional and produce
small amounts of urine.
10. After 10 weeks!
! the mesonephric excretory units cease to function and then
regress. The mesenephric ducts regress in the female, but in the male the
mesonephric ducts plus a few modified mesonephric tubules persist and
form parts of the male genital duct system (we will talk about in more detail in the
next lecture).
C. Metanephroi or the definitive kidneys.
1. 4th week (day 28)!
! the distal portion of the mesonephric ducts sprout ureteric
buds (eventually differentiates into the ureters and the collecting duct system
of the kidneys) which induce the metanephroi to form in the intermediate
mesoderm of the sacral region (Fig 10-4A).
2. Day 32!
! each ureteric bud penetrates the metanephric blastema (a portion of
the sacral intermediate mesoderm which appears around the same time) and
begins to bifurcate (Fig 10-4B). The metanephros become lobulated in
appearance as each ampulla (growing tip of each bifurcated branch) acquires a
caplike aggregate of metanephric blastema tissue. The metanephric blastema
eventually differentiate into the nephrons (the definitive urine-forming units of the
kidneys).
3. Middle of 6th week!
! the developing metanephros consists of two lobes
separated by a sulcus (Fig 10-4C).
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4. By the end of the 16th week!
! the metanephros consists of 14 to 16 lobes (Fig
10-4D) and the sulci between the lobes begin to fill in.
Note: The ureteric bud and metanephric blastema exert reciprocal
inductive effects (classic model of induction). Several hours of direct contact
with a ureteric bud ampulla are required to induce nephron differentiation in
blastema tissue and the reciprocal inductive signals from the metanephric
blastema regulate the orderly bifurcation of the tips of the ureteric buds
(discussed in more detail below). If the ureteric bud is abnormal or missing,
the kidney does not develop.
II. Collecting duct system (entirely the product of the ureteric bud) of the
Metanephroi.
Note: The collecting duct system is produced by sequential bifurcation of the
ureteric bud. Urine produced by the nephrons flows through the collecting tubules,
minor calyces, major calyces, the renal pelvis , and finally, the ureter. This path is
called the collecting duct system.
A. Sequence of bifurcations (Fig 10-5 & Fig 10-6A).
1. Middle of the 4th week!
! when the ureteric bud first contacts the metanephric
blastema, its tip expands to form an initial ampulla that will give rise to the renal
pelvis.
2. 6th week!
! the ureteric bud bifurcates four times, yielding 16 branches which
coalesce to form two to four major calyces extending from the renal pelvis.
! the next four generations of branches also coalesce to form the
3. 7th week!
minor calyces.
4. By 32 weeks!
! 11 additional generations of bifurcation have formed 1 to 3
million branches. These will become the future collecting tubules (collecting
ducts) of the kidney (Fig 10-6A).
B. Nephron development (Fig 10-6B-F).
1. Each nephron originates as a vesicle within the blastemic cap (surrounding the
ampulla of a collecting duct) (Fig 10-6B). The vesicle elongates into a tubule.
And a capillary glomerulus forms near one end of it.
2. The tubule epithelium near the differentiating glomerulus thins and then
invaginates to form a Bowman’s capsule (surrounds the glomerulus).
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3. Just as in the mesonephros, the renal corpuscle consists of a Bowman’s
capsule and the glomerulus.
4. As the renal corpuscle is developing, the lengthening nephric tubule differentiates
into the proximal convoluted tubule, the descending and ascending limbs of
the loop of Henle, and the distal convoluted tubule.
5. The definitive nephron with its renal corpuscle is called a metanephric
excretory unit.
6. By the 10th week!
! the tips of the distal convoluted tubules connect to the
collecting ducts. The metanephroi become functional. Blood plasma from the
glomerular capillaries is filtered by the renal corpuscle to produce a dilute
glomerular filtrate. The filtrate is concentrated and converted to urine by the
convoluted tubules and the loop of Henle. The urine then passes down the
collecting system into the ureters and then the bladder.
Note: The main function of the fetal kidneys is not to clear waste (mainly
handled by the placenta), but instead it supplements the production of
amniotic fluid. Thus fetuses with bilateral renal agenesis do not make enough
amniotic fluid (oligohydramnios), confining the fetus to an abnormally small
amniotic space.
C. Definitive kidney architecture (Fig 10-7).
! the definitive kidney architecture is created.
1. 5th to 15th weeks!
2. The kidney is divided into an inner medulla (contains the collecting ducts and
the loops of Henle) and an outer cortex (contains the nephrons).
3. Each minor calyx drains a tree of collecting ducts within the renal pyramid that
converge to form the renal papilla.
4. The renal pyramids of the kidney are separated by renal column/columns of
Bertin (cortical tissue that contains nephrons). Thus the cortical tissue covers
the outside of the kidney, as well as projecting towards the pelvis.
5. The nephrons arise from the cortical regions of the primary lobes of the
metanephric blastema.
Note: Neural Crest contribute to the function of the Kidney. Neural crest
cells invade the metanephroi early in their development. The neural crest give
rise to the neurons of the kidney that regulate blood flow and secretory function.
These neurons are located at the tips of the metanephric tissue caps during
nephron induction. Thus these neurons also play a role in the induction of
nephron formation.
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III. Kidneys ascend from a sacral to lumbar location.
A. Movement of the Kidneys.
1. 6th to 9th weeks!
! the kidneys ascend to a lumbar site just below the suprarenal
glands. They follow a path on either side of the dorsal aorta (Fig 10-8).
2. The mechanism responsible for the relocation of the kidneys is poorly
understood. The differential growth of the lumbar and sacral regions of the
embryo may play a role.
3. The ascending Kidney is progressively revascularized by a series of arterial
sprouts from the dorsal aorta, and the original renal artery in the sacral region
disappears (Fig 8-6).
Note: The right kidney usually does not rise as high as the left kidney because
of the liver on the right side.
B. Anomalies can arise during the ascent of the kidneys.
1. Some of the transient inferior renal arteries occasionally fail to regress. This
results in the presence of accessory renal arteries.
2. Also, rarely, a kidney completely fails to ascend, remaining as a pelvic kidney
(Fig 10-8C).
3. A U-shaped horseshoe kidney (crosses over the ventral side of the aorta) may
also arise if the inferior poles of the two metanephroi fuse during the ascent.
This causes the kidney to become caught under the inferior mesenteric artery
and subsequently it does not reach its normal site (Fig 10-8D).
IV. The remainder of the urinary tract develops form the hindgut endoderm.
A. Cloacal expansion and partition.
1. As mentioned last week, the cloacal expansion of the hindgut is partitioned by
the urorectal septum into an anterior primitive urogenital sinus and a posterior
rectum (Fig 10-9).
2. The primitive urogenital sinus is continuous superiorly with the allantois (a
hindgut diverticulum that extends into the umbilicus) and is bounded inferiorly by
the urogenital membrane.
3. The primitive urogential sinus consists of a superior presumtive bladder,
pelvic urethrea (the narrow neck), and an inferior definitive urogenital sinus.
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4. In males, the pelvic urethra becomes the membranous and prostatic urethra
and the definitive urogenital sinus becomes the penile urethra.
5. In females, the pelvic urethra becomes the membranous urethra, and the
definitive urogenital sinus becomes the vestibule of the vagina.
B. Exstrophy of the mesonephric ducts and ureteric buds (Fig 10-10).
1. Weeks 4 to 6!
! Via the process of exstropy, the distal portions of the
mesonephric ducts and attached ureteric ducts become incorporated into the
posterior wall of the presumptive bladder (Fig 10-10).
2. Exstropy refers to the eversion of a hollow organ. During this process the
mouths of the mesonephric ducts flare, expand, flatten, and blend into the
bladder wall.
3. This process brings the openings of the ureteric buds into the bladder wall,
while the opening of the mesonephric duct is carried inferiorly to the level of
the pelvic urethra. The mesonephric ducts open into the pelvic urethra just
below the neck of the bladder.
4. The triangular region of exstrophied mesonephric duct, which was incorporated
into the posterior bladder wall, forms the trigone of the bladder. Endoderm from
the surrounding bladder wall grows over the trigone, but it remains visible in the
adult as a smooth triangular region lying between the openings of the ureters
laterally and superiorly, and the opening of the pelvic urethra inferiorly.
5. 12th week!
! Splanchnopleuric mesoderm associated with the hindgut forms
the smooth muscle of the bladder wall.
V. Clinical applications of urinary tract development.
A. Ureteric bud or metanephros defects.
Note: 10% of all newborns have a developmental abnormality of the urinary tract
(most do not cause clinical problems). 45% of childhood renal failure result form
defective development of the ureteric bud or metanephros. Since there is a
reciprocal induction between the ureteric buds and the metanephric blastema,
abnormalities in one often cause abnormalities in the other.
1. Partial duplication of the the ureter! If the ureteric bud prematurely bifurcates
it results in a Y-shaped bifid ureter (Fig 10-23). Although the two branches of
the Y arise from the same ureteric bud, the contractions of their muscular walls
appear to be asynchronous. This may result in stagnate urine that
predisposes the individual to infections of the ureter.
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Could an individual remain asymptomatic and how could this occur?
2. Ectopic ureter (complete duplication)!
! complete duplicate ureters result from
the growth of two ureteric buds. In this condition a mesonephric duct sprouts two
ureteric buds, which penetrate the metanephric blastema indepently (Fig 10-24).
a. The more caudal bud induces the formation of the caudal pole. During
exstrophy, the caudal bud incorporates into the bladder wall normally
(forms a normal orthotopic, ureter connected to the bladder).
b. The more cranial bud induces formation of the cranial pole of the kidney.
During exstrophy, the cranial bud is carried inferiorly along with the
descending mesonephric duct. It may form its final connection with any
derivative of the distal mesonephric duct, pelvic urethra, or definitive
urogenital sinus. Thus it forms an inferior ectopic ureter.
c. In males, the ectopic ureter may drain into the prostatic urethra, the
ejaculaotry duct, the vas deferens, or the siminal vesicle. Thus they always
open superior to the sphincter urethra muscle and do not result in
incontinence (but still can result in painful urination or recurrent infections).
d. In females, ectopic ureters oftern connect to the vestibule, the vagina, or the
uterus (rarely), forming extrasphincteric outlets. This results in
incontinence, but can be surgically corrected.
Note: The normal ureter drains the lower pole of the kidney and the ectopic
ureter drains the upper pole. The observation that the resulting two ureters cross
each other (called the Weigert-Meyer rule) helped to deduce the mechanism of
mesonephric duct exstrophy.
B. Ureteric bud or metanephros induction defects.
1. Renal agenesis.
a. Defects in the inductive interaction between the ureteric bud and metanephric
blastema may cause renal agenesis.
b. In the absence of inductive signals from the ureteric bud, the metanephros
fails to develop. Infants with bilateral renal agenesis are stillborn or die
within a few days after birth. If unilateral renal agenesis occurs the
remaining kidney will become hypertrophic to compensate for the missing
kidney.
c. 75% of the cases involving renal agenesis occur in males.
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d. Renal agenesis typically causes other congenital defects. Since the kidneys
initially contribute to the production of amniotic fluid, bilateral renal agenesis
results in oligohydramnios. The insufficient amniotic fluid causes the uterine
wall to compress the growing fetus, resulting in Potter’s syndrome
(deformed limbs and facial defects—receding chin, low set ears, and parrotbeak nose).
e. Unilateral renal agenesis is usually associated with heart defects and
constrictions of the gastrointestinal tract.
2. Hypoplasia or dysplasia.
a. Subtle defects in the interaction between the ureteric bud and the
metanephric blastema can result in hypoplasia or dysplasia of the developing
kidney.
b. Renal dysplasia!
! nephrons develop abnormally, consisting of primitive
ducts lined by undifferentiated epithelium which is surrounded by connective
tissue.
C. Congenital polycystic kidney disease (ADPKD or ARPKD).
1. AD=Autosomal dominant
2. AR=Autosomal recessive
3. This disease is characterized by small multifocal lesions of the proximal
convoluted tubules, and dialation and cyst formation in the collecting system
(leads to destruction of the surrounding renal parenchyma)
4. ARPKD also results in severe abnormalities of the hepatic collecting ducts and
biliary system.
D. Wilms’ tumor causes nephroblastoma and genetal system defects.
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Urogenital System Development
Genital System Development
I. The genital and urinary systems develop in close conjunction.
Review note: During the 5th week, the primordial germ cells migrate from the yolk
sac via the dorsal mesentery to the mesenchyme of the posteriror body wall (10th
thoracic level) (Fig 10-11A). The primordial germ cells induce cells in the
mesonephros and adjacent coelomic epithelium to proliferate and form the genital
ridges (Fig 10-11B,C & 10-12).
A. Primitive sex cord development.
1. As mentioned above the primitive sex cords develop from mesonephros cells
and coelomic epithelium cells. During the 6th week, these cells invade the
region of the presumptive gonads to form the primitive sex cords which
completely invest the germ cells (Fig 10-11B).
2. At this point the sex cords have a cortical and medullary regions. After the 6th
week these regions pursue different fates in the male and female.
B. Paramesonephric duct (Mullerian) development.
1. During the 6th week, a thickend region of coelomeic epithelium (from the third
thoracic segment caudally to the posterior wall of the urogenital sinus) undergoes
craniocaudal invagination (Fig 10-11B,C), forming the paramesonephric
(mullerian) ducts just lateral to the mesonephric ducts in both male and
female embryos.
2. These ducts are enclosed in the basement membrane of the adjacent
mesonephric ducts.
3. The caudal tips of the paramesonephric ducts connect with the pelvic urethra
(the tips adhere to each other before they connect) just medial to the openings of
the right and left mesonephric ducts, while the superior ends form funnelshaped
openings into the coelom.
4. Further development of the paramesonephric ducts will be discussed later in the
lecture.
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C. Virtually identical male and female genital systems (before end of 6th week).
1. In both sexes, germ cells and sex cords are present in both the cortical and the
medullary regions of the presumptive gonads.
2. Complete mesonephric and paramesonephric ducts are present.
3. After the end of the 6th week the ambisexual or indifferent phase of genital
development ends.
4. 7th week, the male and female systems follow diverging pathways.
II. Basis of sex differentiation.
A. Autosomes and Sex Chromosomes.
1. There is a total complement of 46 chromosomes, 22 pairs consist of matching,
homologous chromosomes called autosomes. The remaining two
chromosomes are called the sex chromosomes because they determine the
sex of the individual.
2. XX individuals are genetically female and XY individuals are genetically male.
Although the pattern of sex chromosomes determines the choice between
male and female developmental paths, the subsequent phases of sexual
development are controlled by both the sex chromosome genes and by the
hormones and factors encoded by the autosomes.
3. The sex-determining region of the Y chromosome (SRY) encodes a
transcription factor that controls the choice between the male and female
developmental paths.
4. When SRY is expressed in the sex cord cells (in the indifferent phase) male
development is triggered (Fig 10-13).
5. Thus, femaleness is the default pathway unless maleness is actively induced.
III. Male genital (internal) development.
A. Sertoli cell differentiation in the medullary sex cords.
1. The SRY protein causes cells within the medullary region of the primitive sex
cords to begin to differentiate into Sertoli cells, while the cells of the cortical sex
cords degenerate (Fig 10-13 & 10-14).
2. If SRY is absent the sex cords develop into ovarian follicles.
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3. 7th week!
! differentiating Sertoli cells organize to form the testis cords (Fig 1014). Also, the testis begins to round up, reducing its area of contact with the
mesonephros (a feminizing influence). As the testes continue to develop, the
degenerating cortical sex cords become separated from the coelomic epithelium
by the tunica albuginea (intervening connective tissue).
4. At pubery!
! testosterone surge! the testis cords and associated germ cells
become canalized and differentiate into the seminiferous tubules. The distal
testis cords develop lumina and differentiate into a set of thin-walled ducts called
the rete testis.
5. The tubules of the rete testis become connected with 5 to 12 residual
mesonephric tubules. The mesonephric ducts become the spermatic ducts
or vasa deferentia (vas deferens, singular).
B. Anti-Mullerian hormone secretion by the pre-Sertoli cells.
1. As the Sertoli cells begin to differentiate in response to the SRY protein, they
also begin to secrete anti-Mullerian hormone (AMH) or Mullerian-inhibiting
substance (MIS) (glycoprotein). The protein region resembles the transforming
growth factor-beta molecule which has been implicated in mesoderm induction
and angiogenesis.
2. 8th to 10th week!
!AMH causes the paramesonephric (mullerian) ducts to
regress in the male (Fig 10-13 &10-14).
3. Paramesonephric duct remnants go on to form the appendix testis and
utriculus prostaticus in the adult male. In female embryos, the
paramesonephric ducts do not regress.
Note: Freemartin calves (female calves that shared a womb with a male twin).
At the time they postulated that some substance (now known as AMH) from the
male circulated in the blood, causing the female to be sterile (has ovaries, but
lacks the derivatives of the paramesonephric ducts).
Clinical note: Some genetic male humans have persistant paramesonephric
ducts because AMH production is deficient or the paramesonephric ducts do not
respond to normal AMH levels. This indicates that paramesonephric duct
regression is an active process rather than a cessation in growth.
4. 9th week!
! the SRY protein (expressed by the pre-Sertoli cells) also initiates a
cascade that induces the differentiation of mesenchymal cells within the genital
ridges into testosterone-secreting Leydig cells (in the testis) (Fig 10-13).
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5. The Leydig cells (endocrine cells) produce testosterone and this early
secretion is regulated by chorionic gonadotropin, secreted by the placenta
(later in development the pituitary gonadotropins of the male fetus take over
control).
C. Differentiation of the mesonephric ducts of the male.
1. 8th to 12th week!
! the initial secretion of testosterone stimulates the
mesonephric ducts to transform into the spermatic ducts (vasa deferentia) (Fig
10-14).
2. The most cranial end of each mesonephric duct degenerates into the
appendix epididymis.
3. The region of the vas deferens adjacent to the presumptive testis differentiates
into the convoluted epididymis.
4. During the 9th week, 5 to 12 mesonephric ducts in the region of the epididymis
make contact with the cords of the future rete testis. 3rd month, these
epigenital mesonephric tubules actually unite with the presumptive rete
testis. After uniting the epigenital mesonephric tubules are then called the
ductuli efferentes. They provide a pathway from the seminiferous tubules and
rete testis tubules to the vas deferens.
5. The mesonephric tubules at the inferior pole of the developing testis
(paragenital mesonephric tubules) degenerate into the paradidymis.
D. Differentiation of the accessory glands of the male urethra.
1. Three accessory glands of the male genital system all develop near the junction
between the mesonephric ducts and the pelvic urethra (Fig 10-15).
! The glandular seminal vesicles sprout from the distal
2. 10th week!
mesonephric duct near their attachment to the pelvic urethra. The portion of
the vas defenens (mesonephric duct) distal to each seminal vesicle is called the
ejaculatory duct.
3. 10th week!
! The prostate gland develops from a cluster of endodermal
evaginations that bud from the pelvic urethra (induced by
dihydrotestoterone). The initial prostatic outgrowths form five solid prostatic
cords. By the 11th week, the cords develop a lumen and glandular acini (the
surrounding mesenchyme differentiates into the smooth muscle and connective
tissue of the prostate) and by the 13th to 15th weeks, as the testosterone
concentrations reach a high level, the prostate begins to secrete.
4. 10th week!
! The paired bulbourethral glands sprout from the urethra (inferior
to the prostate). The mesenchyme surrounding the endodermal glandular tissue
differentiates into the smooth muscle and connective tissue of the bulbourethral
gland.
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Note: The secretions of the seminal vesicles, prostate, and bulbourethral glands
all contribute to the seminal fluid that protects and nourishes the spermatozoa
after ejaculation (not absolutely necessary for sperm function).
IV. Female genital (internal) development.
A. Absence of a Y chromosome.
1. The female sex cord cells do not express SRY protein (they do not contain
the Y chromosome/SRY region) and thus do not differentiate into Sertoli cells.
As a result, AMH, Leydig cells, and testosterone are not produced. The
formation of male structures are not induced, causing the embryo to follow the
default pathway of female development (Fig 10-16).
2. In genetic females, the primitive sex cords degenerate and the mesothelium of
the genital ridge forms secondary sex cords which invest the primordial germ
cells to form the follicle cells of the ovary (Fig 10-16).
Review note: The female germ cells enter meiosis, but further development is
inhibited by the follicle cells. In males, the pre-Sertoli cells inhibit germ cell
development before they enter meiosis. In the female fetus, the germ cells
differentiate into oogonia and enter the first meiotic division as primary oocytes.
The follicle cells then arrest germ cell development until puberty. The close
contact of the genital ridge and mesonephros in females is important for
inducing the initial stages of gamete maturation.
B. Absence of AMH in the female embryo.
1. The mesonephric ducts and mesonephric tubules require testosterone for
their development. Thus, in the female, they rapidly disappear, forming two
remnants, the epoophoron and paroophoron (found in the mesentery of the
ovary). Also, a scattering of tiny remnants called Gartner's cysts cluster near
the vagina (Fig 10-16, 10-17C)
2. The paramesonephric ducts develop uninhibited.
3. The wall of the pelvic urethra (where the growing tips of the paramesonephric
ducts adhere) forms a slight thickening called the sinusal tubercle (Fig 10-17A).
While fusing with the sinusal tubercle the caudal tips of the paramesonephric
ducts fuse in a superior direction (3rd to 5th month), forming the genital canal or
uterovaginal canal (superior portion of the vagina and uterus) (Fig 1017B,C).
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4. The superior portions of the unfused paramesonephric ducts become the
fallopian tubes (oviducts), and the funnel-shaped superior openings of the
paramesonephric ducts become the infundibula of the oviducts (Fig10-16).
5. Also during the 3rd month, the thickening endodermal tissue of the sinusal
tubercle in the posterior urethra forms a pair of swellings called the sinuvaginal
bulbs (gives rise to the inferior 20 percent of the vagina)(Fig 10-17).
6. The vaginal plate (of unkown origin, occludes the most inferior region of the
uterovaginal canal) elongates and becomes canalized by a process of
desquamation (cell shedding) to form the inferior vaginal lumen (3rd to 5th
month).
7. While the vaginal plate forms, the lower end of the vagina lengthens caudally
until it reaches the posterior wall of the definitive urogenital sinus (4th month)
(Fig 10-17C).
8. An endodermal membrane temporarily separates the lumen of the vagina from
the cavity of the definitive urogenital sinus (vestibule of the vagina). After the
5th month, this membranes degenerates into the vaginal hymen.
V. External genitalia development.
A. Male and Female external genitalia develop from the same primordia (Fig 10-18A).
1. Early 5th week!
! the cloacal folds (a pair of swellings) develop on either side of
the cloacal membrane (Fig 10-18A). They meet anterior to the cloacal
membrane, forming the genital tubercle (a midline swelling).
2. The perineum (formed by the fusion of the urorectal septum and cloacal
membrane during the 7th week) divides the cloacal membrane into an anterior
urogenital membrane and a posterior anal membrane.
3. The clocal fold flanking the urogenital membrane is called the urethral fold
(genital/urogenital fold) and the fold flanking the anal membrane is called the
anal fold (Fig 10-18A).
4. The labioscrotal swellings then appear on either side of the urethral folds (Fig
10-18A).
5. Male and Female genitalia are morphologically indistinguishable at this
stage. The appearance of the external genitalia is similar in male and female
embryos through the 12th week.
6. These presumptive genital precursors develop into the male and female genital
structures (Table 10-1).
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B. Male external genitalia (Fig 10-18B).
1. The urogenital folds fuse and the genital tubercle elongates to form the shaft
and glans of the penis.
2. The perineal region separating the definitive urogenital sinus from the anus
begins to lengthen (does not occur in females).
3. Fusion of the urogenital folds encloses the definitive urogenital sinus to form
most of the penile urethra (enclosed by 14 weeks). An alternative mechanism
of closure has been proposed in which the penile urethra is enclosed by an
anterior growth of perineal mesoderm (no involvement of the genital folds).
4. 6th week!
! the extending cavity of the definitive urogenital sinus meets with the
enlarging genital tubercle, forming an endodermal-lined urethral grove (Fig 1018B). The grove eventually forms a temporary urethral plate (solid endoderm)
which recanalizes to form a deep groove. In males, the groove is long and
broad. In females, the groove is short and tapered.
5. A small region of the distal urethra is formed by the invagination of the
ectoderm covering the glans.
6. The labioscrotal folds give rise to the scrotum.
C. Female external genitalia (Fig 10-18C).
1. Since there is no dihydrotestosterone in female embryos, the primitive
perineum does not lengthen and the labioscrotal and urethral folds do not
fuse across the midline (Fig 10-18C).
2. The phallus (elongated genital tubercle) bends inferiorly, becoming the glans
and shaft of the clitoris (Fig 10-18C).
3. The definitive urogenital sinus becomes the vestibule of the vagina.
4. The urethral (urogenital) folds remain separated to form the labia minora, and
the labioscrotal folds (swellings) become the labia majora.
VI. The gubernaculum controls the descent of the testes and ovaries.
A. Gubernaculum.
1. Both testes and ovaries descend from the 10th thoracic level. The testes
eventually descend much farther than the ovaries.
2. In both sexes, the descent of the gonad depends on a ligamentous cord called
the gubernaculum.
3. 7th week!
! the gubernaculum condenses within the subserous fascia of a
longitudinal peritoneal fold on ether side of the vertebral column (Fig 10-19).
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4. The superior end of the gubernaculum attaches to the gonad and the inferior
end (gubernaculum bulb) attaches to the fascia in the region of the labioscrotal
swellings.
5. 8th week, the processus vaginalis or vaginal process (evagination of the
peritoneum) develops just adjacent to the inferior root of the gubernaculum.
6. In males, the inguinal canal is formed when the vaginal process pushes out a
socklike evagination of the abdominal wall. The vaginal process pushes through
the transversalis fascia (gives rise to the internal spermatic fascia of the
spermatic cord), the internal oblique muscle (gives rise to the cremasteric
fascia of the spermatic cord), and the external oblique muscle (becomes the
external spermatic fascia). As the vaginal process elongates caudally it
brings along the bulb of the gubernaculum. Eventually, the vaginal process
degenerates.
B. The descent of the testes (Fig 10-19).
1. In the male the inguinal canal extends into the scrotum and transmits the
descending testes. In females a complete inguinal canal also forms, but it does
not play a role in female genital development.
2. The inguinal canal is considered as a series of weakenings (deep ring—
weakening of the transversalis fascia and the superficial ring—weakening of the
external oblique muscle) in the layers of the abdominal wall (Fig 10-19D). These
stretched out layers allow the testes to descend into the scrotum.
3. The testes descend to the deep ring of the inguinal canal by the third month and
complete their descent in the seventh to ninth months.
4. 7th to 12th weeks, the extrainguinal portions of the gubernacula shorten (first
phase—shorten by getting flatter at their base) and pull the testes down to
the deep ring (enlarges the inguinal canal). The testes remain in the vicinity of
the deep ring from the 3rd to 7th month.
5. 7th to 9th month, second phase of shortening occurs by actual reduction and
regression of the gubernaculum (testosterone and other androgens are
important for the second phase). The descent of the testes is also aided by the
increased abdominal pressure (which results from the growth of the abdominal
viscera).
Clinical note: The superior region of the vaginal process degenerates leaving a
distal remnant called the tunical vaginalis (anterior to the testis) (Fig 10-20 &
Fig 10-21). Normally the lumen is collapsed, but under pathologic conditions it
may fill with serous secretions, forming a testicular hydrocele (Fig 10-20B, D).
Also, occasionally the entire vaginal process remains, forming an indirect
inguinal hernia (connection between the abdominal cavity and the scrotal sac)
(Fig 10-20C). Inguinal hernias also can occur in females. Repair of these
hernias is the second most common childhood operation.
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C. The descent of the ovaries (Fig 10-22).
1. The female embryo also forms a gubernaculum. It is attached at the inferior pole
of the gonad and extends to the presumptive labioscrotal folds and abdominal
wall (this forms the female inguinal canal).
2. In the female, the gubernaculum does not shorten or regress, but it still
causes the ovaries to descend during the 3rd month, sweeping them into the
broad ligament of the uterus (Fig 10-22 & Fig 10-17). The ovaries move
because the paramesonephric ducts (which are attached to the gubernaculum)
fuse and pull the broad ligaments into the peritoneal folds.
3. The inferior gubernaculum becomes the round ligament of the uterus
(connects the fascia of the labia majora to the uterus).
4. The superior gubernaculum becomes the ligament of the ovary (connects the
uterus to the ovary).
VII. Clinical Applications.
A. Variable phenotypes of Wilms’ Tumor.
1. Denys-Drash syndrom (DDS)!
!severe abnormalities of the gonads and
external genetalia.
2. WAGR syndrome!
!Wilm’s tumor, aniridia (lack of irises), genital abnormalities,
and mental retardation.
3. Beckwith-Wiedemann syndrome!
!renal hyperplasia and Wilms’ tumor
(individuals lack the normal genomic imprinting that inactivates the IGF-2 gene
on the paternal chromosome.
B. Defective partitioning of the cloaca.
1. Failure of the Rathke fold to develop (Rectourethra fistuals) (Fig 10-26)!In
males, they form a rectoprostatic urethral fistula (Fig 10-26C). In females, a
rectocloacal canal (Fig 10-26D), a rectovaginal fistula (Fig 10-26E), or an
anovestibular fistula can form.
2. Failure of both Rathke and Tourneux fold development!causes a more
severe defect in which the rectum and the bladder are connected (rectovesical
fistula) (Fig 10-27).
3. Malalignment of the Tourneux and Rathke folds! results in a urorectal
fistula (Fig 10-28).
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C. Anal malformations (result form maldevelopment of the anal pit, anal membrane or
genital folds).
1. Anal agenesis (Fig 10-29A)!causes rectum to end blindly in the body wall.
2. Imperforate anal membrane! caused by a thickened anal membrane that
failed to rupture (Fig 10-29B).
3. Anal stenosis! caused by an incomplete rupture of the anal membrane.
D. Abnormal development of the genital system.
Note: Most genital system malformations arise from alterations in autosomal genes.
1. Pseudohermaphroditism (external genitalia of one sex accompany the gonads
of the other)! caused by sex hormone anomalies. The block of which male
hormone would cause external genital feminization?
2. The most common manifestation of male pseudohermaphroditism is
hypospadias (urethra opens onto the ventral surface of the penis (Fig 10-30A,
B). A more complex condition (penoscrotal hypospadias) occurs when the
labioscrotal swellings, as well as the urethral folds fail to fuse (urethra is open
through a hole between the base of the penis and the root of the scrotum) (Fig 130C,D). The block of which hormone, dihydrotestosterone or testosterone,
results in perminant feminization of the male genitalia? Why?
3. Testicular feminization syndrome!
! the androgen receptors are abnormal,
resulting in the formation of a blind-ending vagina. Since the testes are still
present and AMH is produced, the paramesonephric ducts regress.
4. Female pseudohermaphroditism!
! is very rare. These individuals exhibit
clitoral hypertrophy and fusion of the urethral and labioscrotal folds. Because the
testes and AMH are absent the vagina, uterus , and fallopian tubes develop
normally.
5. True hermaphrodites have both ovarian and testicular tissue. The gonads are
usually a composite ovotestes containing both seminiferous tubules and
follicles. Or an individual may have an ovary on one side and a testes on the
other side. Most true hermaphrodites are reared as males since a phallus is
usually present at birth.
6. Primary hypogonadism!
! is caused by a gonadal defect. The gonads do not
respond to the gonadotropins and thus do not increase production of sex steroids
at puberty. Thus the individual fails to enter puberty. In males, primary
hypogonadism is usually caused by Klinefelter syndrome (extra X
chromosome). In females, primary hypogonadism is usually associated with
Turner syndrome (missing X chromosome).
7. Secondary hypogonadism!
! is caused by defects of the hypothalamus or
anterior pituitary. These individuals have depressed levels of both gonadotropins
and sex steroids and thus do not enter puberty.
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