The development of the head and neck, as well as of the embryo in general, is the result of extensive cellular migrations that form virtually all of the skeletal, muscular and glandular structures. The mechanisms that underlie the initiation, directionality and cessation of cell migrations are responsible for the most common congenital malformation, and are just now beginning to be elucidated. During the previous support period, a novel molecular mechanism for mesenchymal cell interactions with the underlying basal lamina was identified. Results show that cell surface beta1, 4-galactosyltransferase I (GT I) is expressed on the leading and trailing edges of migrating cells, where it is associated with the cytoskeleton, facilitating cell spreading and migration. Altering the expression of GT I on the cell surface positively leads to decreased cell migration, while decreased GT I expression leads to increased rates of cell migration, due to the cells becoming either overly adhesive or loosely adhesive to the basal lamina substratum. The binding site for GT I in the basal lamina has been identified as N-linked glycosides in the E8 domain of laminin. The relative degree of stability of lamellipodia can be altered by GT I association with the cytoskeleton. GT I may also catalytically release from its oligosaccharide-binding site in laminin. GTI is expressed on the growth cones of developing neurites where it facilitated neurite outgrowth. Increasing GT I expression leads to increased rates of neurite formation. GTI is expressed on the cell surface of metastatic cells, and down-regulating GT I expression or adding GT I perturbants can inhibit metastasis in vivo. Clustering of GT I by multivalent ligands induces a transient phosphorylation of FAK, leading to depolymerization of stress fibers, presumably facilitating cell migration. GT is expressed on the leading edge of migrating neural crest cells, and microinjection of anti-GT IgG inhibits the migration of neural crest cells in vivo. However, GT I-null mice have grossly normal facial development, suggesting the presence of other matrix receptors that compensate for the loss of GT I. In this renewal application, the function of the newly identified GT isoform (GT II - GT VI) during craniofacial morphogenesis will be addressed. Also, the spectrum of cytosolic proteins that associate with GT I, enabling it to function as a signal transducing receptor for glycoside ligands, will be defined.
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