Third to Eighth Week:
The Embryonic Period
The embryonic period or period of organogenesis,occurs from thethird to the eighth weeksof devel-opment and is the timewhen each of the three germ layers, ectoderm, mesoderm, andendoderm, gives rise to a number of specific tissues and organs. By the end of the embryonic period, the main organ systems have been established, rendering the major features of the external body form recognizable by the end of the second month.
Derivatives of the Ectodermal Germ Layer
At the beginning of the third week of development, the ectodermal germ layer has the shape of a disc that is broader in the cephalic than the caudal region. Appearance of the notochord and prechordal mesoderm induces the overlying ectoderm to thicken and form the neural plate. Cells of the plate make up the neuroectoderm and their induction represents the initial event in the process of neurulation.
MOLECULAR REGULATION OF NEURAL INDUCTION
Blocking the activity of BMP-4,a TGF-βfamily member responsible for ventralizing ectoderm and mesoderm, causes induction of the neural plate. Thus, in the presence of BMP-4, which permeates the mesoderm and ectoderm of the gastrulating embryo, ectoderm becomes epidermis, and mesoderm forms intermediate and lateral plate mesoderm. If BMP-4 is absent or inactivated, ectoderm becomes neuralized. Secretion of three other molecules,noggin, chordin,andfollistatin, inactivates this protein. These three proteins are present in the organizer (primitive node), notochord, and prechordal mesoderm. They neuralize ectoderm and cause mesoderm to become notochord and paraxial mesoderm (dorsalizesmesoderm). However, these neural inducers induce only forebrain and midbrain types of tissues. Induction of caudal neural plate structures (hindbrain and spinal cord) depends upon two secreted proteins,WNT-3aandFGF (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 ones by regulating expression of homeobox genes.
Once induction has occurred, the elongated, slipper-shaped neural plate gradually expands toward the primitive streak. By the end of the third week, the lateral edges of the neural plate become more elevated to form neural folds,and the depressed midregion forms the neural groove. Gradually, the neural folds approach each other in the midline, where they fuse. Fusion begins in the cervical region (fifth somite) and proceeds cranially and caudally. As a result,the neural tubeis formed. Until fusion is complete, the cephalic and caudal ends of the neural tube communicate with the amniotic cavity by way of the cranial and caudal neuropores,respectively. Clo-sure of the cranial neuropore occurs at approximately day 25 (18- to 20-somite stage), whereas the posterior neuropore closes at day 27 (25-somite stage).Neurulation is then complete, and the central nervous system is represented by a closed tubular structure with a narrow caudal portion, thespinal cord,and a much broader cephalic portion characterized by a number of dilations,the brain vesicles.
As the neural folds elevate and fuse, cells at the lateral border or crest of the neuroectoderm begin to dissociate from their neighbors. This cell population,the neural crest, will undergo an epithelial-to-mesenchymal transition as it leaves the neuroectoderm by active migration and displacement to enter the underlying mesoderm. (Mesodermrefers to cells derived from the epiblast and extraembryonic tissues.Mesenchyme refers to loosely organized embryonic connective tissue regardless of origin.) Crest cells from the trunk region leave the neural folds after closure of the neural tube and migrate along one of two pathways:
1) a dorsal pathway through the dermis, where they will enter the ectoderm through holes in the basal lamina to form melanocytesin the skin and hair follicles and
2) a ventral pathway through the anterior half of each somite to become sensory ganglia, sympathetic and enteric neurons, Schwann cells and cells of the adrenal medulla. Neural crest cells also form and migrate from cranial neural folds, leaving the neural tube before closure in this region. These cells contribute to the craniofacial skeleton as well as neurons for cranial ganglia, glial cells, melanocytes,and other cell types. Induction of neural crest cells requires an interaction between adjacent neural and overlying ectoderm.Bone morphogenetic proteins (BMPs),secreted by non-neural ectoderm, appear to initiate the induction process. Crest cells give rise to a heterogeneous array of tissues, as indicated in By the time the neural tube is closed, two bilateral ectodermal thickenings,The otic placodes and the lens placodes,become visible in the cephalic region of the embryo. During further development, the otic placodes invaginate and form the otic vesicles,which will develop into structures needed for hearing and maintenance of equilibrium. At approximately the same time, the lens placo desappear. These placodes also invaginate and, during the fifth week, form the lenses of the eyes.
In general terms, the ectodermal germ layer gives rise to organs and structures that maintain contact with the outside world: (a) the central nervous system; (b) the peripheral nervous system; (c) the sensory epithelium of the ear, 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 pituitary gland, and enamel of the teeth.
Mesodermal Germ Layer
Initially, cells of the mesodermal germ layer form a thin sheet of loosely woven tissue on each side of the midline. By approximately the17th day, however, cells close to the midline proliferate and form a thickened plate of tissue known as paraxial mesoderm. More laterally, the mesoderm layer remains thin and is known as the lateral plate.With the appearance and coalescence of intercellular cavities in the lateral plate, this tissue is divided into two layers :
(a)a layer continuous with mesoderm covering the amnion, known as the somatic or parietal mesoderm layer and (b) a layer continuous with mesoderm covering the yolk sac, known as the splanchnic or visceral mesoderm layer. Together, these layers line a newly formed cavity, the intraembryonic cavity, which is continuous with the extraembryonic cavity on each side of the embryo.Intermediate mesoderm connects paraxial and lateral plate mesoderm.
By the beginning of the third week, paraxial mesoderm is organized into segments. These segments, known as somitomeres,first appear in the cephalic re-gion of the embryo, and their formation proceeds cephalocaudally. Each somitomere consists of mesodermal cells arranged in concentric whorls around the center of the unit. In the head region, somitomeres form in association with segmentation of the neural plate into neuromeresand contribute to mesenchyme in the head. From the occipital region caudally, somitomeres further organize into somites. The first pair of somites arises in the occipital region of the embryo at approximately the 20th day of develop-ment. From here, new somites appear in craniocaudal sequence at a rate of approximately three pairs per day until, at the end of the fifth week, 42 to 44 pairs are present. There are four occipital, eight cervical, 12 thoracic, five lumbar, five sacral, and eight to 10 coccygeal pairs. The first occipital and the last five to seven coccygeal somites later disappear, while the remaining somites form the axial skeleton. During this period of development, the age of the embryo is expressed in number of somites.the approximate age of the embryo correlated to the number of somites.By the beginning of the fourth week, cells forming the ventral and me-dial walls of the somite lose their compact organization, become polymor-phous, and shift their position to surround the notochord .
These cells, collectively known as thesclerotome,form a loosely woven tissue,the mesenchyme.They will surround the spinal cord and notochord to form the vertebral column. Cells at the dorsolateral portion of the somite also migrate as precursors of the limb and body wall musculature. After migration of these muscle cells and cells of the sclerotome,cells at the dorsomedial portion of the somite proliferate and migrate down the ventral side of the remaining dorsal epithelium of the somite to form a new layer, the myotome. The remaining dorsal epithelium forms the dermatome, and together these layers constitute the dermomyotome. Each segmentally arranged myotome contributes to muscles of the back (epaxial musculature), while dermatomes disperse to form the dermis and subcutaneous tissue of the skin. Further more each myotome and dermatome retains its innervation from its segment of origin, no matter where the cells migrate. Hence each somite forms its own sclerotome(the cartilage and bone component), its ownmyotome(providing the segmental muscle component), and its own dermatome,the segmental skin component. Each myotome and dermatome also has its own segmental nerve component.
Intermediate mesoderm, which temporarily connects paraxial mesoderm with the lateral plate, differentiates into urogenital struc-tures. In cervical and upper thoracic regions, it forms segmental cell clusters (futurenephrotomes), whereas more caudally, it forms an unsegmented mass of tissue, the nephrogenic cord.Excretory units of the urinary system and the gonads develop from this partly segmented, partly unsegmented intermediate mesoderm.
LATERAL PLATE MESODERM
Lateral plate mesoderm splits into parietal and visceral layers, which line the intraembryonic cavity and surround the organs, respectively. Mesoderm from the parietal layer, together with overlying ectoderm, will form the lateral and ventral body wall. The visceral layer and embryonic endoderm will form the wall of the gut. Mesoderm cells of the parietal layer surrounding the intraembryonic cavity will form thin membranes, the mesothelial membranes,orserous membranes,which will line the peritoneal, pleural, and pericardial cavities and secrete serous fluid. Mesoderm cells of the visceral layer will form a thin serous mem-brane around each organ.