The long term goal of this study is to elucidate the roles of cell-cell and cell-matrix adhesion receptors in the regulation of the salivary submandibular gland (SMG) development. SMG develops through branching morphogenesis from an epithelial bud into a tree-like structure consisting of an array of ducts terminating in secretory acini. SMG morphogenesis involves cycles of growth and new bud formation that are tightly coordinated with the expansion and branching of ductal structures. The regulatory signals that guide the specification, expansion and differentiation of acinar and ductal progenitors into an organized three dimensional structure are largely unknown. Because cell-cell and cell-matrix interactions have been shown to regulate morphogenetic changes during epithelial tissue development, we have focused on E-cadherin, a principal salivary cell-cell adhesion receptor, and 1321 integrin, the receptor for laminin, a major component of the basement membrane in the SMG. Our studies have shown that the patterns of acinar and ductal cell fate are established at the initial bud stage and maintained throughout morphogenesis. Acinar progenitors are restricted to the peripheral cell layer in contact with the basement membrane, while the interior bud cells comprise proliferating ductal progenitors and non-proliferating differentiating duct cells. E-cadherin is required for diverse functions of these cells during SMG morphogenesis. In the acinar progenitor cells, E-cadherin junctions are stabilized through the interaction with 1321 integrin to regulate the coordination of acinar progenitor cell proliferation with new bud formation. Similar mechanism for stabilization of E-cadherin junctions is found in renal cells, where 1321 integrin organizes multiprotein scaffolds. Our studies also show that the mass producing proliferating ductal progenitors maintain immature E-cadherin junctions by the activity of Src. Later in morphogenesis, Src appears to be counteracted by the recruitment of phosphatases, SHP2 and/or PTP< to promote duct formation. During duct development, stable E-cadherin junctions signal differentiation and protection from apoptotic death most likely through the activation of PI3K/Akt pathway. Our hypothesis is that E-cadherin-mediated functions in different aspects of SMG morphogenesis and differentiation are regulated by association with structural and signaling molecules. We propose to test this hypothesis by investigating the mechanisms underlying changes in E-cadherin adhesive activity in distinct cell populations during SMG morphogenesis in three aims: 1) examine whether 1321 integrin stabilizes E-cadherin junctions in the acinar progenitor cells through the recruitment of scaffold proteins; 2) examine if coordination of SMG growth with ductal cell differentiation involves regulation of E-cadherin function by Src and subsequent signaling from E-cadherin junctions to PI3 kinase; and 3) examine the hypothesis that protein phosphatases regulate E-cadherin cell-cell contacts during maturation of salivary cells in the developing SMG. Diseases of the salivary glands, including cancer and Sjogren's Syndrome, are characterized by the disruption of cell-matrix and cell-cell adhesion. Our studies focus on the functions of cell-cell and cell-matrix adhesion receptors and their regulation during salivary gland development. Understanding how these adhesion receptors drive morphogenetic events is essential for the design of effective therapeutics that will target diseased salivary tissues, as well as for the bioengineering of salivary glands and tissue replacement. ? ? ?
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