We hypothesize that the basement membrane (BM) receptor dystroglycan (DG) mediates critical signals in epithelial cell development, homeostasis and tissue-specific functions. DG has been studied most extensively in muscle tissues, where loss of DG function has been implicated in muscular dystrophies, but investigation of DG functions in epithelia has lagged. Information emerging from recent studies in epithelial cells has implicated DG in a wide range of cell responses to the BM, including cell polarization, cell survival, BM organization, and tissue-specific gene expression. But inconsistencies exist between results from different experimental systems, and DG's roles in epithelial tissues remain poorly defined, as do the signaling mechanisms by which DG mediates its functions. Importantly, alterations in the cell-BM interactions play important roles in cancer progression, and loss of DG function is evident in carcinoma cells. Therefore, DG functions in epithelial cell also have potential high relevance to human pathology. To assess the roles of DG in epithelial cells, we have established a unique system for the genetic manipulation of DG function in cultured mammary epithelial cells using cells derived from the """"""""floxed DG"""""""" (flanking-Lox DG) transgenic mouse line. These cells allow selective deletion of DG gene expression in functionally normal cells through """"""""Cre-/Lox"""""""" recombination, permitting direct comparisons of DG +/+ and DG-/- cells in assays of normal cell behavior and signal transduction. Using this experimental system we will: 1) determine the cell responses induced by DG signaling in cultured mammary epithelial cells; 2) determine the consequence of loss of DG signaling in cells exposed to the in vivo microenvironment; and 3) dissect the signaling pathways emanating from DG that are responsible for identified receptor functions. A thorough evaluation of DG roles in mammary epithelial cells will advance our basic understanding of how cell-BM interactions regulate normal epithelial cell behavior. A thorough assessment of DG signaling in epithelial cells is also necessary to understand the signaling imbalances that result from the frequent loss of this BM receptor in cancer progression.
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