Cell adhesion, migration, and morphogenesis are crucial events in craniofacial development, and errors in them can produce congenital anomalies. Similar processes appear to be important for normal adult wound repair. Molecules that mediate or regulate these processes are being characterized. Fibronectin is important for both morphogenesis and epithelial wound healing, e.g. for migration of craniofacial neural crest cells. Regions of fibronectin essential for cell adhesion and migration were characterized in detail by site-directed mutagenesis, homology scanning, and monoclonal antibody approaches. The sequence Pro-His-Ser- Arg-Asn was shown to be essential for cell adhesion mediated by the alpha5beta1 fibronectin receptor, and the Arg residue was crucial. This information should facilitate the rational design of novel bioadhesives and inhibitors. Although fibronectin could not be implicated in embryonic nephric duct extension, NCAM polysialic acid appeared to be involved. Vitronectin is another major extracellular adhesion molecule. Analysis of mRNA expression was striking in the spinal cord floor plate of mouse embryos. This structure is important for neuronal development, and vitronectin may be a novel effector molecule. Adhesion, migration, and morphogenesis are regulated by a variety of factors including cytokines and receptors, such as the c-met proto-oncogene receptor. We discovered and further characterized a novel spliced version of this tyrosine kinase receptor, which we found to be a multi-functional regulatory region involving PKC responsiveness, PI 3-kinase binding, and tyrosine phosphorylation. This and other receptors have been implicated in the inter-conversion of epithelia and mesenchyme in development. We showed novel regulation of splicing and function of this family of receptors. We have identified two candidate genes involved in the process of epithelial- mesencymal transition, one of which appears to trigger this important process. These studies should provide a molecular understanding of the regulation of these important but complex morphogenetic processes.
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