C

Notochordal plate

Notochordal plate

Intraembryonic Endoderm mesoderm

Intraembryonic Endoderm mesoderm

Intraembryonic mesoderm

Intraembryonic mesoderm

Intraembryonic Endoderm

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

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

Notochord Formation

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).

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 ft (TGF-ft) 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-ft family, bone morphogenetic protein-4 (BMP-4) 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

Goosecoid, chordin, noggin, follistatin, nodal

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.

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.

Cross Section Mouse Embryonic Node
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-3j3 maintains the node and later induces regional specificity in the forebrain and midbrain areas. Without HNF-3ft, 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

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.

Buccopharyngeal

Buccopharyngeal

Buccopharyngeal End

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 p (TGF-p) 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.

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 p (TGF-p) 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. 4.9 A). 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 sided-ness (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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