The cellular behavior involved in morphogenesis are regulated by molecules at cell surfaces that bind cells to the extracellular matrix and to other cells. Epithelial cells contain a cell surface proteoglycan that is a high affinity receptor specific for interstitial matrix materials. The proteoglycan appears to stabilize epithelial sheets by physically linking the intracellular cytoskeleton with the matrix produced by mesenchymal cells. Recent results lead to the working hypothesis that the core protein of the cell surface proteoglycan, the protein to which the glycosaminoglycan chains are covalently bound, is a developmentally regulated molecule that functions as a matrix receptor or as a cell adhesion molecule depending on its post-translational modifications. As a matrix receptor, it would contain heparan and chondroitin sulfate chains, be expressed late in development and, in mature tissues, be solely on the basolateral surface of simple epithelial cells. As a cell adhesion molecule, it would be less extensively glycosylated, be expressed early in development and, in mature tissues, surround stratified epithelial cells. During embryogenesis, it would be present on both epithelial and mesenchymal cells, but change its expression in association with morphogenetic events. This application is designed to explore the hypothesis that the epithelial cell surface proteoglycan is a developmentally regulated multifunctional adhesion molecule.
The specific aims are to: (i) evaluate the regulation of cell surface proteoglycan expression in early mouse embryos and during subsequence morphogenetic events by immunological and molecular assessments of its time of appearance, cell and tissue localization, post- translational modifications and mRNA level, (ii) test whether the cell surface proteoglycan functions as a cell adhesion molecule by attempting to perturb cell aggregation and histogenesis with defined antibodies and ligands, to isolate an endogenous ligand(s) and comparing its modifications in simple and stratified epithelia, (iii) define the matrix receptor role by examining whether it traverses the basal lamina, comparing its function with other receptors, evaluating whether it mediates receptor-specific cellular responses and generating cells that are deficient or enhanced in the cell surface proteoglycan. Knowledge of the mechanisms involved in cell-cell and cell-matrix adhesion is critically important to an understanding of cell behavior during development and neoplastic invasion. This research will provide new insight into these mechanisms, potentially leading to diagnosis, treatment and ultimately, prevention of birth defects and metastases.
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