Placental Villi

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 meso-derm (the other source of this tissue is the primitive yolk sac [hypoblast]; see p. 55).

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

Embryonic Germ LayersBasal Cell Scanning Electron Prostate

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.

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.

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.

Caudal Dysgenesis
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

Prenotochordal Cells
Figure 4.14 Sacrococcygeal teratoma resulting from remnants of the primitive streak. These tumors may become malignant and are most common in females.
Sacrococcygeal Teratoma Type

villus villus villus

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 ofthe villus showing a number of capillaries and venules.

villus villus villus

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 ofthe villus showing a number of capillaries and venules.

Cytotrophoblastic Shell

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 intraembry-onic vessels.

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 intraembry-onic 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.

Placenta Tertiary Villi

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.

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 gas-trulation, 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 noto-chordal 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,

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-ft 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).

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).

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