Chapter Summary

A number of cells leave their original location and migrate to new locations in a developing embryo. A classic example is that of Primordial Germ Cells (PGCs) in the developing metazoan embryo. It is now known that the homing of PGCs involves Receptor Tyrosine Kinases (RTKs). In fact PGCs in the mouse embryo express the RTK encoded by the W gene, and the ligand encoded by the steel gene is expressed by cells along their migratory pathway. Mutations in either of these genes lead to deficiencies in the directed migration of PGCs. Another group of cells that shows pronounced directed migration is the neural crest cells. These cells follow specific trajectories sometimes over long distances, to their final locations, and a particular pathway of differentiation is realised at the final location. It is sometimes presumed that changes in the adhesive properties of cells must take place. Emigrating neural crest cells show reduced levels of N- and E- cadherins and later show reduced levels of N-CAMs. Thus reduced adhesivity might be important for crest migration. Furthermore, the ephrin-Eph-receptor system has been implicated in regulating the migration of neural crest cells in the developing embryo. This signaling system is thought be crucial in limiting the migration of neural crest cells through the rostral half of the somite.

A splendid example of morphogenetic movements is the directed migration of a neurite. The advancing tip of the neurite, called the growth cone, is an area of considerable motility. The growth cone is composed of filopodia and lamellipodia, which constitute the pathfinding apparatus of the neurite by way of its dynamic explorations of its surroundings. Neurite outgrowth may be regulated by any of four modes: stereotaxis, contact inhibition, haptotaxis, or chemotaxis. Molecules responsible for directed growth cone migration have been identified. For example Netrin-1 and -2 are responsible for the growth of efferent neurites of commissural neurons toward the floor plate. Netrins are called chemoattractants since their presence in the ventral regions of the spinal cord allows the migration of neurites into this region. On the other hand, molecules that behave as chemorepellents have also been identified; semaphorins form one such family of chemorepellent molecules. They generally act to guide the extension of efferent neurites, whose growth cones are repelled from areas where semaphorins are concentrated.

Outgrowth of the limb during development is dependent on reciprocal interactions between epithelial and mesenchymal cells. The initial formation of the AER (chapter 7) requires signals from the lateral plate mesoderm; these signaling interactions may be brought about by BMP family molecules. The AER is crucial in regulating limb outgrowth. According to the current model, FGF10 from the underlying mesoderm signals to the overlying epithelium to form the AER, which in turn produces FGF8, thereby leading to limb bud outgrowth. Another instance where epithelial-mesenchymal interactions come into play is lung development. Molecules that mediate these interactions are those belonging to the FGF and TGF family. Furthermore, the extracellular matrix molecules and their associated cellular integrins play important roles in these signaling interactions. Much of what we have learned about the matrix and basal lamina has come from studies of the salivary glands. The branching of salivary glands requires the presence of glycosaminoglycans as well as collagen, and it is regulated by ligands such as FGF. Kidney morphogenesis also requires a complex set of interactions between tissues. For example, glial derived neurotrophic factor (GDNF) stimulates epithelial growth, and thus ureteric bud proliferation, by binding to its receptor, which is a heterodimeric RTK. Other signaling molecules involved in kidney morphogenesis are FGF2, WNT11, and BMP7.

Gastrulation entails many different complex morphogenetic movements of tissue. It has been well studied in sea urchins which possess the unique advantage of having embryos with excellent optical clarity. At the end of cleavage, the blastula is a single cell layer thick. A few micromere derived cells at the vegetal pole ingress from the epithelium. This involves the reduction of adhesivity to each other and to the gelatinous extracellular matrix that overlays them. They achieve this mainly by reducing the amount of cadherins they express. Ingression of the primary mesenchymal cells is followed by the formation of the archenteron. Cells at the advancing tip of the archenteron become extremely active, forming filopodia and ultimately making contact with the epithelium at the blastocoel surface. They then become intimately connected with the blastocoel wall, and this area will eventually form a perforation that becomes the mouth of the larva.

Gastrulation in Xenopus is marked by the invagination of bottle cells, which is initiated by their apical constriction and the subsequent elongation of their cell bodies as they protrude into the interior. Consequently the endodermal core forces the marginal zone cells outward and toward the vegetal pole. The deep subsurface mesodermal cells then undergo involution. Bottle cells, however, are not essential for the process of gastrulation per se. Gastrulation is mainly driven by convergence and extension of the involuting cells. Convergence and extension involve the mediolateral intercalation of cells. The noninvoluting surface ectodermal cells undergo epiboly, which is the flattening of cells, thus allowing their spread over the embryo. Convergent extension of cells results in the extension of the axis in the anterior-posterior direction. The anterior extension of the converged and involuted mesoderm occurs along the blastocoel roof. This movement of the mesoderm is dependent on fibronectin in the extracellular matrix. Thus a complex set of cellular behaviors contribute to gastrulation in Xenopus.

Studies on Drosophila gastrulation mutants have led to identification of a number of genes that play a role in the process. For example, folded gastrulation (fog) is involved in the formation of wedge-shaped cells that drive invagination. Other molecules involved in similar processes are those encoded by drhoGEF2 and concertina.


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