This proposal concerns the molecular basis by which fibronectins influence maturation in the skin. This family of closely related glycoproteins is abundant in mammalian skin throughout development and postnatal life, especially within the dermis, the connective tissue sheaths of nerve, blood vessel and muscle fibers within the dermis and the dermal-epidermal junction and other basement membranes. Previous data suggest that fibronectins, through their ability to influence cellular behavior, are important extracellur matrix molecules. They can specifically promote cell-matrix adhesion and facilitate migration, processes inherently involved in skin development and repair. The molecular control of these processes is, however, not well understood. Since fibronectins are multi- domain molecules, able to interact with collagens, proteoglycans and cell surfaces we hypothesize that it is the controlled interaction of its constituent domains which modulate adhesive responses to fibronectins, to allow migration or firm anchorage. Through the use of purified fibronectin domains, specific antibodies, synthetic peptide analogues of fibronectin and analysis of cell surface molecules potentially involved in modulating cellular interactions with fibronectin, we shall examine how adhesion and migration are controlled in cultured dermal fibroblasts. Fibronectin is synthesized very early in development and is enriched in embryonic basement membranes. However, its distribution with in the human dermal-epidermal junction and changes which may occur in concert with epidermal maturation are unknown. Since many severe skin diseases involve lesions in the basement membrane, documentation of its composition through development is important. We shall use immunoelectron microscopy to map fibronectins in the dermal-epidermal junction. Moreover, our data with an epithelial cell line show that fibronectins may promote basement membrane assembly, a process commensurate with tissue organization and repair. Presently, the molecular mechanism of its action is unknown and we propose to test whether fibronectins 'nucleate' assembly of the basement membrane matrix and/or influence epithelial behavior and promote direct export of matrix components.
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