c h a p t e r
4
Third Week of Development:
Trilaminar Germ Disc
Gastrulation: Formation of Embryonic
Mesoderm and Endoderm
The most characteristic event occurring during
the third week of gestation is gastrulation, the process
that establishes all three germ layers (ectoderm,
mesoderm, and endoderm) in the embryo. Gastrulation begins with formation of the primitive streak on the
surface of the epiblast (Figs. 4.1–4.3A). Initially, the streak
is vaguely defined (Fig. 4.1), but in a 15- to 16-day embryo,
it is clearly visible as a narrow groove with slightly bulging
regions on either side (Fig. 4.2). The cephalic end of the streak,
the primitive node, consists of a slightly elevated area surrounding the small primitive pit (Fig. 4.3). Cells of the epiblast migrate
toward the primitive streak (Fig. 4.3). Upon arrival in the region
of the streak, they become flask-shaped, detach from the epiblast,
and slip beneath it (Fig. 4.3, B–D). This inward movement is known
as invagination. Once the cells have invaginated, some displace the
hypoblast, creating the embryonic endoderm, and others come to lie
between the epiblast and newly created endoderm to form mesoderm.
Cells remaining in the epiblast then form ectoderm. Thus, the epiblast,
through the process of gastrulation, is the source of all of the germ
layers (Fig. 4.3B ), and cells in these layers will give rise to all of the
tissues and organs in the embryo.
As more and more cells move between the epiblast and hypoblast
layers, they begin to spread laterally and cephalad (Fig. 4.3). Gradually,
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Part One: General Embryology
Amniotic
cavity
Syncytiotrophoblast
Epiblast
Hypoblast
Cytotrophoblast
Extraembryonic
mesoderm
Definitive
yolk sac
A
Cut edge of
amnion
Buccopharyngeal membrane
Primitive
streak
B
Wall of
yolk sac
Hypoblast
Epiblast
Figure 4.1 A. Implantation site at the end of the second week. B. Representative view
of the germ disc at the end of the second week of development. The amniotic cavity
has been opened to permit a view on the dorsal side of the epiblast. The hypoblast and
epiblast are in contact with each other and the primitive streak forms a shallow groove
in the caudal region of the embryo.
they migrate beyond the margin of the disc and establish contact with the extraembryonic mesoderm covering the yolk sac and amnion. In the cephalic
direction, they pass on each side of the prechordal plate. The prechordal plate
itself forms between the tip of the notochord and the buccopharyngeal membrane and is derived from some of the first cells that migrate through the
node in a cephalic direction. Later, the prechordal plate will be important for
Chapter 4: Third Week of Development: Trilaminar Germ Disc
67
Figure 4.2 A. Dorsal aspect of an 18-day embryo. The embryo has a pear-shaped appearance and shows the primitive streak and node at its caudal end. B. Photograph of
an 18-day human embryo, dorsal view. Note the primitive node and the notochord extending cranially. The yolk sac has a somewhat mottled appearance. The length of the
embryo is 1.25 mm and the greatest width is 0.68 mm.
induction of the forebrain (Figs. 4.3A and 4.4A). The buccopharyngeal membrane at the cranial end of the disc consists of a small region of tightly adherent
ectoderm and endoderm cells that represents the future opening of the oral
cavity.
Formation of the Notochord
Prenotochordal cells invaginating in the primitive pit move forward cephalad
until they reach the prechordal plate (Fig. 4.4). These prenotochordal cells
become intercalated in the hypoblast so that, for a short time, the midline of the
embryo consists of two cell layers that form the notochordal plate (Fig. 4.4, B
and C ). As the hypoblast is replaced by endoderm cells moving in at the streak,
cells of the notochordal plate proliferate and detach from the endoderm. They
then form a solid cord of cells, the definitive notochord (Fig. 4.4, D and E ),
which underlies the neural tube and serves as the basis for the axial skeleton.
Because elongation of the notochord is a dynamic process, the cranial end
forms first, and caudal regions are added as the primitive streak assumes a
more caudal position. The notochord and prenotochordal cells extend cranially
to the prechordal plate (an area just caudal to the buccopharyngeal membrane)
and caudally to the primitive pit. At the point where the pit forms an indentation
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Part One: General Embryology
Buccopharyngeal
membrane
Cut edge of amnion
Prenotochordal cells
Primitive node
Primitive streak
Cloacal membrane
A
Primitive
node
Primitive
streak
Amnioblasts
Epiblast
Yolk
sac
B
Invaginating
mesoderm cells
Hypoblast
Figure 4.3 A. Dorsal side of the germ disc from a 16-day embryo indicating the movement of surface epiblast cells (solid black lines) through the primitive streak and node
and the subsequent migration of cells between the hypoblast and epiblast (broken lines).
B. Cross section through the cranial region of the streak at 15 days showing invagination of epiblast cells. The first cells to move inward displace the hypoblast to create
the definitive endoderm. Once definitive endoderm is established, inwardly moving epiblast forms mesoderm. C. Scanning electron micrograph through the primitive streak
of a mouse embryo showing migration of epiblast (eb) cells. The node region appears
as a shallow pit (arrow). D. Higher magnification of the section in C.
in the epiblast, the neurenteric canal temporarily connects the amniotic and
yolk sac cavities (Fig. 4.4A).
The cloacal membrane is formed at the caudal end of the embryonic disc
(Fig. 4.3A). This membrane, which is similar in structure to the buccopharyngeal membrane, consists of tightly adherent ectoderm and endoderm cells with
no intervening mesoderm. When the cloacal membrane appears, the posterior
Chapter 4: Third Week of Development: Trilaminar Germ Disc
C
D
D
Figure 4.3—Continued.
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Part One: General Embryology
Primitive pit and
neurenteric canal
Connecting stalk
Amnion
Ectoderm
B
C
Allantois
Wall of
yolk sac
Notochord
Prechordal plate
Cloacal plate
(membrane)
A
Notochordal plate
C
Intraembryonic
mesoderm
Endoderm
Intraembryonic mesoderm
Endoderm
E
Extraembryonic
mesoderm
Notochord
Figure 4.4 Schematic views and scanning electron micrographs illustrating formation
of the notochord, whereby prenotochordal cells migrate through the primitive streak,
become intercalated in the endoderm to form the notochordal plate, and finally detach
from the endoderm to form the definitive notochord. Because these events occur in a
cranial-to-caudal sequence, portions of the definitive notochord are established in the
head region first. A. Drawing of a sagittal section through a 17-day embryo. The most
cranial portion of the definitive notochord has formed, while prenotochordal cells caudal
to this region are intercalated into the endoderm as the notochordal plate. B. Scanning
electron micrograph of a mouse embryo showing the region of the buccopharyngeal
Chapter 4: Third Week of Development: Trilaminar Germ Disc
71
B
D
F
membrane (arrows). Extending posteriorly is the prenotochordal plate (arrowheads).
C. Schematic cross section through the region of the notochordal plate. Soon the
notochordal plate will detach from the endoderm to form the definitive notochord.
D. Scanning electron micrograph of a mouse embryo showing detachment of the notochordal plate from the endoderm. E. Schematic view showing the definitive notochord.
F. Scanning electron micrograph of a mouse embryo showing the definitive notochord
(arrows) in close approximation to the neural tube (NT).
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Part One: General Embryology
wall of the yolk sac forms a small diverticulum that extends into the connecting
stalk. This diverticulum, the allantoenteric diverticulum, or allantois, appears
around the 16th day of development (Fig. 4.4A). Although in some lower vertebrates the allantois serves as a reservoir for excretion products of the renal
system, in humans it remains rudimentary but may be involved in abnormalities of bladder development (see Chapter 14).
Establishment of the Body Axes
Establishment of the body axes, anteroposterior, dorsoventral, and left-right,
takes place before and during the period of gastrulation. The anteroposterior
axis is signaled by cells at the anterior (cranial) margin of the embryonic disc.
This area, the anterior visceral endoderm (AVE), expresses genes essential for
head formation, including the transcription factors OTX2, LIM1, and HESX1
and the secreted factor cerberus. These genes establish the cranial end of the
embryo before gastrulation. The primitive streak itself is initiated and maintained by expression of Nodal, a member of the transforming growth factor β
(TGF-β) family (Fig. 4.5). Once the streak is formed, a number of genes regulate formation of dorsal and ventral mesoderm and head and tail structures.
Another member of the TGF-β family, bone morphogenetic protein-4 (BMP4) is secreted throughout the embryonic disc (Fig. 4.5). In the presence of this
protein and fibroblast growth factor (FGF), mesoderm will be ventralized to
contribute to kidneys (intermediate mesoderm), blood, and body wall mesoderm (lateral plate mesoderm). In fact, all mesoderm would be ventralized if
the activity of BMP-4 were not blocked by other genes expressed in the node.
For this reason, the node is the organizer. It was given that designation by
Goosecoid, chordin,
noggin, follistatin,
nodal
AVE
Figure 4.5 Sagittal section through the node and primitive streak showing the expression pattern of genes regulating the craniocaudal and dorsoventral axes. Cells at the
prospective cranial end of the embryo in the anterior visceral endoderm (AVE) express
the transcription factors OTX2, LIM1, and HESX1 and the secreted factor cerberus that
contribute to head development and establish the cephalic region. Once the streak is
formed and gastrulation is progressing, bone morphogenetic protein (BMP-4; hatched
areas), secreted throughout the bilaminar disc, acts with FGF to ventralize mesoderm
into intermediate and lateral plate structures. Goosecoid regulates chordin expression,
and this gene product, together with noggin and follistatin, antagonizes the activity
of BMP-4, dorsalizing mesoderm into notochord and paraxial mesoderm for the head
region. Later, expression of the Brachyury (T) gene antagonizes BMP-4 to dorsalize
mesoderm in caudal regions of the embryo.
Chapter 4: Third Week of Development: Trilaminar Germ Disc
73
Figure 4.6 Node and primitive streak region removed from a mouse embryo showing
expression of nodal using in situ hybridization. Nodal is expressed in the node and
initiates and maintains the primitive streak.
Hans Spemann, who first described this activity in the dorsal lip of the blastopore, a structure analogous to the node, in Xenopus embryos. Thus, chordin
(activated by the transcription factor Goosecoid ), noggin, and follistatin antagonize the activity of BMP-4. As a result, cranial mesoderm is dorsalized into
notochord, somites, and somitomeres (Fig. 4.5). Later, these three genes are
expressed in the notochord and are important in neural induction in the cranial
region.
As mentioned, Nodal is involved in initiating and maintaining the primitive streak (Fig. 4.6). Similarly, HNF-3β maintains the node and later induces
regional specificity in the forebrain and midbrain areas. Without HNF-3β, embryos fail to gastrulate properly and lack forebrain and midbrain structures. As
mentioned previously, Goosecoid activates inhibitors of BMP-4 and contributes
to regulation of head development. Overexpression or underexpression of this
gene results in severe malformations of the head region, including duplications
(Fig. 4.7).
Regulation of dorsal mesoderm formation in mid and caudal regions of the
embryo is controlled by the Brachyury (T) gene (Fig. 4.8). Thus, mesoderm
formation in these regions depends on this gene product, and its absence
results in shortening of the embryonic axis (caudal dysgenesis; see p. 80).
The degree of shortening depends upon the time at which the protein becomes
deficient.
Left-right sidedness, also established early in development, is orchestrated
by a cascade of genes. When the primitive streak appears, fibroblast growth
factor 8 (FGF-8) is secreted by cells in the node and primitive streak and
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Part One: General Embryology
Figure 4.7 Two-headed tadpole produced by injecting additional Goosecoid mRNA into
frog eggs. Similar results can be obtained by transplanting an additional node region
to eggs. Goosecoid is normally expressed in the node and is a major regulator of head
development.
Figure 4.8 Expression pattern of the Brachyury (T) gene in the notochord and primitive
streak of a mouse embryo. This gene antagonizes the activity of bone morphogenetic
protein (BMP-4) in the hindbrain and spinal cord regions and dorsalizes mesoderm to
form notochord, somitomeres, and somites (paraxial mesoderm). (Mouse embryos are
dorsiflexed into a cup shape during the period of gastrulation and neurulation.) nf,
neural fold; hp, head process; ps, primitive streak; al, allantois.
Chapter 4: Third Week of Development: Trilaminar Germ Disc
75
Buccopharyngeal
membrane
FGF8
Neural
tube
Nodal
Lefty2
PITX2
Nodal
Notochord
(SHH, T)
Lefty 1
Node
Nodal
NKX3.2
FGF8
Node
(FGF8)
A
Cloacal
membrane
B
Figure 4.9 Dorsal views of the germ disc showing gene expression patterns responsible for establishing the left-right body axis. A. Fibroblast growth factor 8 (FGF-8),
secreted by the node and primitive streak, establishes expression of Nodal, a member of the transforming growth factor β (TGF-β) superfamily, on the left side near
the node. B. Later, as the neural plate is induced, FGF-8 induces expression of Nodal
and Lefty-2 in the lateral plate mesoderm, whereas Lefty-1 is expressed on the left
side of the ventral aspect of the neural tube. Products from the Brachyury (T) gene,
expressed in the notochord, also participate in induction of these three genes. In
turn, expression of Nodal and Lefty-2 regulates expression of the transcription factor PITX 2, which, through further downstream effectors, establishes left sidedness.
Sonic hedgehog (SHH), expressed in the notochord, may serve as a midline barrier and
also repress expression of left-sided genes on the right. NKX 3.2 may regulate downstream genes important for establishing right sidedness.
induces expression of Nodal but only on the left side of the embryo (Fig. 4.9A).
Later, as the neural plate is induced, FGF-8 maintains Nodal expression in the
lateral plate mesoderm (Fig. 4.10), as well as Lefty-2, and both of these genes
upregulate PITX2, a transcription factor responsible for establishing left sidedness (Fig. 4.9B). Simultaneously, Lefty-1 is expressed on the left side of the
floor plate of the neural tube and may act as a barrier to prevent left-sided signals from crossing over. Sonic hedgehog (SHH ) may also function in this role
as well as serving as a repressor for left sided gene expression on the right. The
Brachyury(T) gene, another growth factor secreted by the notochord, is also
essential for expression of Nodal, Lefty-1, and Lefty-2 (Fig. 4.9B ). Genes regulating right-sided development are not as well defined, although expression of the
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Part One: General Embryology
A
B
Figure 4.10 Expression pattern of the gene nodal in a mouse showing that it is restricted to the left side of the body (A) in the lateral plate mesoderm (B). Nodal, together
with Lefty, regulates downstream genes to determine left-right asymmetry.
transcription factor NKX 3.2 is restricted to the right lateral plate mesoderm
and probably regulates effector genes responsible for establishing the right side.
Why the cascade is initiated on the left remains a mystery, but the reason may
involve cilia on cells in the node that beat to create a gradient of FGF-8 toward
the left. Indeed, abnormalities in cilia-related proteins result in laterality defects
in mice and some humans with these defects have abnormal ciliary function
(see p. 79).
Fate Map Established During Gastrulation
Regions of the epiblast that migrate and ingress through the primitive streak
have been mapped and their ultimate fates determined (Fig. 4.11). For example, cells that ingress through the cranial region of the node become notochord;
those migrating at the lateral edges of the node and from the cranial end of
the streak become paraxial mesoderm; cells migrating through the midstreak
region become intermediate mesoderm; those migrating through the more
caudal part of the streak form lateral plate mesoderm; and cells migrating
through the caudal-most part of the streak contribute to extraembryonic mesoderm (the other source of this tissue is the primitive yolk sac [hypoblast]; see
p. 55).
Chapter 4: Third Week of Development: Trilaminar Germ Disc
77
Figure 4.11 Dorsal view of the germ disc showing the primitive streak and a fate map
for epiblast cells. Specific regions of the epiblast migrate through different parts of the
node and streak to form mesoderm. Thus, cells migrating at the cranial-most part of the
node will form the notochord (n); those migrating more posteriorly through the node and
cranial-most aspect of the streak will form paraxial mesoderm (pm; somitomeres and
somites); those migrating through the next portion of the streak will form intermediate
mesoderm (im; urogenital system); those migrating through the more caudal part of the
streak will form lateral plate mesoderm (lpm; body wall); and those migrating through
the most caudal part will contribute to extraembryonic mesoderm (eem; chorion).
Growth of the Embryonic Disc
The embryonic disc, initially flat and almost round, gradually becomes elongated, with a broad cephalic and a narrow caudal end (Fig. 4.2). Expansion
of the embryonic disc occurs mainly in the cephalic region; the region of the
primitive streak remains more or less the same size. Growth and elongation of
the cephalic part of the disc are caused by a continuous migration of cells from
the primitive streak region in a cephalic direction. Invagination of surface cells
in the primitive streak and their subsequent migration forward and laterally
continues until the end of the fourth week. At that stage, the primitive streak
shows regressive changes, rapidly shrinks, and soon disappears.
That the primitive streak at the caudal end of the disc continues to supply
new cells until the end of the fourth week has an important bearing on development of the embryo. In the cephalic part, germ layers begin their specific
differentiation by the middle of the third week (Fig. 4.12), whereas in the caudal
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Part One: General Embryology
Figure 4.12 A. Scanning electron micrograph (dorsal view) of a mouse embryo (equivalent to human at approximately 18 days), showing initial elevation of the cranial neural folds (CF ). The primitive streak lies farther caudally and is obscured from view. B.
Transverse section through the embryo shown in A (see line of section). Note three germ
layers; pseudostratified columnar cells of the neuroectoderm (Ec), flattened endoderm
(En), and mesoderm (Me) sandwiched between these two layers. Asterisks, mitotic cells.
Chapter 4: Third Week of Development: Trilaminar Germ Disc
79
part, differentiation begins by the end of the fourth week. Thus gastrulation,
or formation of the germ layers, continues in caudal segments while cranial
structures are differentiating, causing the embryo to develop cephalocaudally
(Fig. 4.12).
CLINICAL CORRELATES
Teratogenesis Associated With Gastrulation
The beginning of the third week of development, when gastrulation is initiated,
is a highly sensitive stage for teratogenic insult. At this time, fate maps can
be made for various organ systems, such as the eyes and brain anlage, and
these cell populations may be damaged by teratogens. For example, high
doses of alcohol at this stage kill cells in the anterior midline of the germ disc,
producing a deficiency of the midline in craniofacial structures and resulting
in holoprosencephaly. In such a child, the forebrain is small, the two lateral
ventricles often merge into a single ventricle, and the eyes are close together
(hypotelorism). Because this stage is reached 2 weeks after fertilization, it is
approximately 4 weeks from the last menses. Therefore, the woman may not
recognize she is pregnant, having assumed that menstruation is late and will
begin shortly. Consequently, she may not take precautions she would normally
consider if she knew she was pregnant.
Gastrulation itself may be disrupted by genetic abnormalities and toxic
insults. In caudal dysgenesis (sirenomelia), insufficient mesoderm is formed
in the caudal-most region of the embryo. Because this mesoderm contributes
to formation of the lower limbs, urogenital system (intermediate mesoderm),
and lumbosacral vertebrae, abnormalities in these structures ensue. Affected
individuals exhibit a variable range of defects, including hypoplasia and fusion
of the lower limbs, vertebral abnormalities, renal agenesis, imperforate anus,
and anomalies of the genital organs (Fig. 4.13). In humans, the condition is
associated with maternal diabetes and other causes. In mice, abnormalities
of Brachyury (T), Wnt, and engrailed genes produce a similar phenotype.
Situs inversus is a condition in which transposition of the viscera in the
thorax and abdomen occurs. Despite this organ reversal, other structural abnormalities occur only slightly more frequently in these individuals. Approximately 20% of patients with complete situs inversus also have bronchiectasis
and chronic sinusitis because of abnormal cilia (Kartagener syndrome). Interestingly, cilia are normally present on the ventral surface of the primitive node
and may be involved in left-right patterning during gastrulation. Other conditions of abnormal sidedness are known as laterality sequences. Patients with
these conditions do not have complete situs inversus but appear to be predominantly bilaterally left sided or right sided. The spleen reflects the differences;
those with left-sided bilaterality have polysplenia, and those with right-sided
bilaterality have asplenia or hypoplastic spleen. Patients with laterality sequences also are likely to have other malformations, especially heart defects.
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Part One: General Embryology
Figure 4.13 Sirenomelia (caudal dysgenesis). Loss of mesoderm in the lumbosacral
region has resulted in fusion of the limb buds and other defects.
Tumors Associated With Gastrulation
Sometimes, remnants of the primitive streak persist in the sacrococcygeal
region. These clusters of pluripotent cells proliferate and form tumors, known
as sacrococcygeal teratomas, that commonly contain tissues derived from all
three germ layers (Fig. 4.14). This is the most common tumor in newborns,
occurring with a frequency of one in 37,000. These tumors may also arise
from primordial germ cells (PGCs) that fail to migrate to the gonadal ridge
(see p. 4).
Further Development of the Trophoblast
By the beginning of the third week, the trophoblast is characterized by primary villi that consist of a cytotrophoblastic core covered by a syncytial layer
(Figs. 3.6 and 4.15). During further development, mesodermal cells penetrate
the core of primary villi and grow toward the decidua. The newly formed structure is known as a secondary villus (Fig. 4.15).
By the end of the third week, mesodermal cells in the core of the villus
begin to differentiate into blood cells and small blood vessels, forming the
villous capillary system (Fig. 4.15). The villus is now known as a tertiary villus
Chapter 4: Third Week of Development: Trilaminar Germ Disc
81
Figure 4.14 Sacrococcygeal teratoma resulting from remnants of the primitive streak.
These tumors may become malignant and are most common in females.
Figure 4.15 Development of a villus. A. Transverse section of a primary villus showing
a core of cytotrophoblastic cells covered by a layer of syncytium. B. Transverse section of
a secondary villus with a core of mesoderm covered by a single layer of cytotrophoblastic
cells, which in turn is covered by syncytium. C. Mesoderm of the villus showing a number
of capillaries and venules.
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Part One: General Embryology
Figure 4.16 Longitudinal section through a villus at the end of the third week of development. Maternal vessels penetrate the cytotrophoblastic shell to enter intervillous
spaces, which surround the villi. Capillaries in the villi are in contact with vessels in the
chorionic plate and in the connecting stalk, which in turn are connected to intraembryonic vessels.
or definitive placental villus. Capillaries in tertiary villi make contact with
capillaries developing in mesoderm of the chorionic plate and in the connecting
stalk (Figs. 4.16 and 4.17). These vessels, in turn, establish contact with the
intraembryonic circulatory system, connecting the placenta and the embryo.
Hence, when the heart begins to beat in the fourth week of development, the
villous system is ready to supply the embryo proper with essential nutrients
and oxygen.
Meanwhile, cytotrophoblastic cells in the villi penetrate progressively into
the overlying syncytium until they reach the maternal endometrium. Here they
establish contact with similar extensions of neighboring villous stems, forming
a thin outer cytotrophoblast shell (Figs. 4.16 and 4.17). This shell gradually
surrounds the trophoblast entirely and attaches the chorionic sac firmly to the
maternal endometrial tissue (Fig. 4.17). Villi that extend from the chorionic
plate to the decidua basalis (decidual plate: the part of the endometrium
where the placenta will form; see Chapter 6) are called stem or anchoring
villi. Those that branch from the sides of stem villi are free (terminal) villi,
through which exchange of nutrients and other factors will occur (Fig. 4.18).
The chorionic cavity, meanwhile, becomes larger, and by the 19th or 20th
day, the embryo is attached to its trophoblastic shell by a narrow connecting
stalk (Fig. 4.17). The connecting stalk later develops into the umbilical cord,
which forms the connection between placenta and embryo.
Chapter 4: Third Week of Development: Trilaminar Germ Disc
83
Figure 4.17 Presomite embryo and the trophoblast at the end of the third week. Tertiary
and secondary stem villi give the trophoblast a characteristic radial appearance. Intervillous spaces, which are found throughout the trophoblast, are lined with syncytium.
Cytotrophoblastic cells surround the trophoblast entirely and are in direct contact with
the endometrium. The embryo is suspended in the chorionic cavity by means of the
connecting stalk.
Summary
The most characteristic event occurring during the third week is gastrulation, which begins with the appearance of the primitive streak,
which has at its cephalic end the primitive node. In the region of the
node and streak, epiblast cells move inward (invaginate) to form new cell layers, endoderm and mesoderm. Hence, epiblast gives rise to all three germ
layers in the embryo. Cells of the intraembryonic mesodermal germ layer
migrate between the two other germ layers until they establish contact with
the extraembryonic mesoderm covering the yolk sac and amnion (Figs. 4.3
and 4.4).
Prenotochordal cells invaginating in the primitive pit move forward until
they reach the prechordal plate. They intercalate in the endoderm as the notochordal plate (Fig. 4.4). With further development, the plate detaches from the
endoderm, and a solid cord, the notochord, is formed. It forms a midline axis,
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Part One: General Embryology
Figure 4.18 Stem villi (SV) extend from the chorionic plate (CP) to the basal plate (BP).
Terminal villi (arrows) are represented by fine branches from stem villi.
which will serve as the basis of the axial skeleton (Fig. 4.4). Cephalic and caudal ends of the embryo are established before the primitive streak is formed.
Thus, cells in the hypoblast (endoderm) at the cephalic margin of the disc form
the anterior visceral endoderm that expresses head-forming genes, including
OTX2, LIM1, and HESX1 and the secreted factor cerberus. Nodal, a member
of the TGF-β family of genes, is then activated and initiates and maintains the
integrity of the node and streak. BMP-4, in the presence of FGF, ventralizes
mesoderm during gastrulation so that it forms intermediate and lateral plate
mesoderm. Chordin, noggin, and follistatin antagonize BMP-4 activity and
dorsalize mesoderm to form the notochord and somitomeres in the head region. Formation of these structures in more caudal regions is regulated by the
Brachyury (T) gene. Left-right asymmetry is regulated by a cascade of genes;
first, FGF-8, secreted by cells in the node and streak, induces Nodal and Lefty-2
expression on the left side. These genes upregulate PITX2, a transcription factor
responsible for left sidedness.
Epiblast cells moving through the node and streak are predetermined by
their position to become specific types of mesoderm and endoderm. Thus, it is
possible to construct a fate map of the epiblast showing this pattern (Fig. 4.11).
Chapter 4: Third Week of Development: Trilaminar Germ Disc
85
By the end of the third week, three basic germ layers, consisting of ectoderm, mesoderm, and endoderm, are established in the head region, and
the process continues to produce these germ layers for more caudal areas of
the embryo until the end of the 4th week. Tissue and organ differentiation has
begun, and it occurs in a cephalocaudal direction as gastrulation continues.
In the meantime, the trophoblast progresses rapidly. Primary villi obtain
a mesenchymal core in which small capillaries arise (Fig. 4.17). When these
villous capillaries make contact with capillaries in the chorionic plate and connecting stalk, the villous system is ready to supply the embryo with its nutrients
and oxygen (Fig. 4.17).
Problems to Solve
1. A 22-year-old woman consumes large quantities of alcohol at a party and
loses consciousness; 3 weeks later she misses her second consecutive period.
A pregnancy test is positive. Should she be concerned about the effects of her
binge-drinking episode on her baby?
2. An ultrasound scan detects a large mass near the sacrum of a 28-week female
fetus. What might the origin of such a mass be, and what type of tissue might
it contain?
3. On ultrasound examination, it was determined that a fetus had well-developed
facial and thoracic regions, but caudal structures were abnormal. Kidneys
were absent, lumbar and sacral vertebrae were missing, and the hindlimbs
were fused. What process may have been disturbed to cause such defects?
4. A child has polysplenia and abnormal positioning of the heart. How might
these two abnormalities be linked developmentally, and when would they have
originated? Should you be concerned that other defects might be present?
What genes might have caused this event, and when during embryogenesis
would it have been initiated?
SUGGESTED READING
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