c h a p t e r 5
Third to Eighth Week:The Embryonic Period
The embryonic period or period of organogenesis,occurs from the third to the eighth weeks of devel-opment and is the time when each of the three germlayers, ectoderm, mesoderm, and endoderm, givesrise to a number of specific tissues and organs. By theend of the embryonic period, the main organ systemshave been established, rendering the major features of
the external body form recognizable by the end of thesecond month.
Derivatives of the EctodermalGerm Layer
At the beginning of the third week of development, the ectodermalgerm layer has the shape of a disc that is broader in the cephalicthan the caudal region (Fig. 5.1). Appearance of the notochord andprechordal mesoderm induces the overlying ectoderm to thicken andform the neural plate (Fig. 5.2). Cells of the plate make up the neu-roectoderm and their induction represents the initial event in theprocess of neurulation.
MOLECULAR REGULATION OF NEURAL INDUCTION
Blocking the activity of BMP-4, a TGF- family member responsiblefor ventralizing ectoderm and mesoderm, causes induction of the
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Figure 5.1 A. Dorsal view of a 16-day presomite embryo. The primitive streak andprimitive node are visible. B. Dorsal view of an 18-day presomite embryo. The embryois pear-shaped, with its cephalic region somewhat broader than its caudal end. C. Dorsalview of an 18-day human embryo. Note the primitive node and, extending forward fromit, the notochord. The yolk sac has a somewhat mottled appearance. The length of theembryo is 1.25 mm, and the greatest width is 0.68 mm.
Chapter 5: Third to Eighth Week: The Embryonic Period 89
Figure 5.2 A. Dorsal view of a late presomite embryo (approximately 19 days). The am-nion has been removed and the neural plate is clearly visible. B. Dorsal view of a humanembryo at approximately 20 days showing somites and formation of the neural grooveand neural folds. C. Scanning electron micrograph of a mouse embryo (approximately20-day human) showing the typical appearance of the neural groove stage. Cranial neu-ral folds have segregated themselves into forebrain (F, prosencephalon), midbrain (M,mesencephalon), and hindbrain (H, rhombencephalon) regions.
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neural plate. Thus, in the presence of BMP-4, which permeates the mesodermand ectoderm of the gastrulating embryo, ectoderm becomes epidermis, andmesoderm forms intermediate and lateral plate mesoderm. If BMP-4 is ab-sent or inactivated, ectoderm becomes neuralized. Secretion of three othermolecules, noggin, chordin, and follistatin, inactivates this protein. Thesethree proteins are present in the organizer (primitive node), notochord, and pre-chordal mesoderm. They neuralize ectoderm and cause mesoderm to becomenotochord and paraxial mesoderm (dorsalizesmesoderm). However, these neu-ral inducers induce only forebrain and midbrain types of tissues. Induction ofcaudal neural plate structures (hindbrain and spinal cord) depends upon twosecreted proteins, WNT-3a and FGF (fibroblast growth factor). In addition,retinoic acid appears to play a role in organizing the cranial-to-caudal axis be-cause it can cause respecification of cranial segments into more caudal onesby regulating expression of homeobox genes (see p. 105).
Once induction has occurred, the elongated, slipper-shaped neural plate grad-ually expands toward the primitive streak (Fig. 5.2, B and C ). By the end of thethird week, the lateral edges of the neural plate become more elevated to formneural folds, and the depressed midregion forms the neural groove (Figs. 5.2,5.3, A and B, and 5.4). Gradually, the neural folds approach each other in themidline, where they fuse (Fig. 5.3C ). Fusion begins in the cervical region (fifthsomite) and proceeds cranially and caudally (Figs. 5.5 and 5.6). As a result,the neural tube is formed. Until fusion is complete, the cephalic and caudalends of the neural tube communicate with the amniotic cavity by way of thecranial and caudal neuropores, respectively (Figs. 5.5, 5.6A, and 5.7). Clo-sure of the cranial neuropore occurs at approximately day 25 (18- to 20-somitestage), whereas the posterior neuropore closes at day 27 (25-somite stage).Neurulation is then complete, and the central nervous system is representedby a closed tubular structure with a narrow caudal portion, the spinal cord,and a much broader cephalic portion characterized by a number of dilations,the brain vesicles (see Chapter 19).
As the neural folds elevate and fuse, cells at the lateral border or crest of theneuroectoderm begin to dissociate from their neighbors. This cell population,the neural crest (Figs. 5.3 and 5.4), will undergo an epithelial-to-mesenchymaltransition as it leaves the neuroectoderm by active migration and displacementto enter the underlying mesoderm. (Mesoderm refers to cells derived from theepiblast and extraembryonic tissues. Mesenchyme refers to loosely organizedembryonic connective tissue regardless of origin.) Crest cells from the trunkregion leave the neural folds after closure of the neural tube and migrate alongone of two pathways: 1) a dorsal pathway through the dermis, where they willenter the ectoderm through holes in the basal lamina to form melanocytes inthe skin and hair follicles; and 2) a ventral pathway through the anterior half ofeach somite to become sensory ganglia, sympathetic and enteric neurons,
Chapter 5: Third to Eighth Week: The Embryonic Period 91
Figure 5.3 Formation and migration of neural crest cells in the spinal cord. A and B.Crest cells form at the tips of neural folds and do not migrate away from this region untilneural tube closure is complete. C. After migration, crest cells contribute to a hetero-geneous array of structures, including dorsal root ganglia, sympathetic chain ganglia,adrenal medulla, and other tissues (Table 5.1). D. In a scanning electron micrographof a mouse embryo, crest cells at the top of the closed neural tube can be seen mi-grating away from this area (arrow). E. In a lateral view with the overlying ectodermremoved, crest cells appear fibroblastic as they move down the sides of the neural tube.(S, somites).
Schwann cells, and cells of the adrenal medulla (Fig. 5.3). Neural crest cellsalso form and migrate from cranial neural folds, leaving the neural tube be-fore closure in this region (Fig. 5.4). These cells contribute to the craniofacialskeleton as well as neurons for cranial ganglia, glial cells, melanocytes, andother cell types (Table 5.1). Induction of neural crest cells requires an interactionbetween adjacent neural and overlying ectoderm. Bone morphogenetic pro-teins (BMPs), secreted by non-neural ectoderm, appear to initiate the induction
92 Part One: General Embryology
Figure 5.4 A. Cross section through the cranial neural folds of a mouse embryo. Neu-ral crest cells at the tip of the folds (arrow) migrate and contribute to craniofacial mes-enchyme. B. Lateral view of the cranial neural folds of a mouse embryo with the surfaceectoderm removed. Numerous neural crest cells can be observed leaving the neuralfolds (NF ) and migrating beneath the ectoderm that has been removed. Unlike crestcells of the spinal cord, cranial crest exits the neural folds before they fuse.
process. Crest cells give rise to a heterogeneous array of tissues, as indicatedin Table 5.1 (see p. 95).
By the time the neural tube is closed, two bilateral ectodermal thickenings,the otic placodes and the lens placodes, become visible in the cephalic regionof the embryo (Fig. 5.8B ). During further development, the otic placodes in-vaginate and form the otic vesicles, which will develop into structures neededfor hearing andmaintenance of equilibrium (see Chapter 16). At approximatelythe same time, the lens placodes appear. These placodes also invaginate and,during the fifth week, form the lenses of the eyes (see Chapter 17).
In general terms, the ectodermal germ layer gives rise to organs and struc-tures that maintain contact with the outside world: (a) the central nervous
Chapter 5: Third to Eighth Week: The Embryonic Period 93
Figure 5.5 A. Dorsal view of a human embryo at approximately day 22. Seven distinctsomites are visible on each side of the neural tube. B. Dorsal view of a human embryoat approximately day 23. Note the pericardial bulge on each side of the midline in thecephalic part of the embryo.
system; (b) the peripheral nervous system; (c) the sensory epithelium of theear, nose, and eye; and (d) the epidermis, including the hair and nails. In addi-tion, it gives rise to subcutaneous glands, the mammary glands, the pituitarygland, and enamel of the teeth.
Derivatives of the Mesodermal Germ Layer
Initially, cells of the mesodermal germ layer form a thin sheet of looselywoven tissue on each side of the midline (Fig. 5.9A). By approximately the17th day, however, cells close to the midline proliferate and form a thick-ened plate of tissue known as paraxial mesoderm (Fig. 5.9B ). More later-ally, the mesoderm layer remains thin and is known as the lateral plate.With the appearance and coalescence of intercellular cavities in the lateralplate, this tissue is divided into two layers (Fig. 5.9, B and C ): (a) a layercontinuous with mesoderm covering the amnion, known as the somatic orparietal mesoderm layer; and (b) a layer continuous with mesoderm cov-ering the yolk sac, known as the splanchnic or visceral mesoderm layer(Figs. 5.9, C and D, and 5.10). Together, these layers line a newly formedcavity,