EPITHELIAL MORPHOGENESIS IN DEVELOPMENT AND DISEASE

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DESCRIPTION (provided by applicant): Epithelia are composed of polarized sheets of cells whose main function is to establish a barrier that protects the body from its environment. Epithelia have a high capacity for renewal and injury repair to maintain this barrier. Unfortunately, epithelial cells are also the most common cell type implicated in cancer. Cadherin-based adherens junctions (AJ) mediate initial epithelial cell-cell adhesion allowing cells to assemble into polarized multicellular tissues. Once formed AJ are not static, however. While much is known about nascent AJ formation the maintenance and remodeling of AJ in a formed epithelia is, in general, a less well-understood process. Rho GTPases are critical regulators of epithelial adhesion, cell shape, and polarization. The ability of Rho GTPases to activate different effectors, in response to cell adhesion, is believed to be responsible for their functional diversity, yet whether certain effectors can be assigned to specific roles and what those roles are, especially in vivo, are uncertain. The presence of multiple Rho GTPase family members and effectors in mammals complicates determination of their function in vivo. In contrast Drosophila have only one Rho and Cdc42 member and most effector proteins have one or few members, allowing for a more straightforward analysis. Over the past 3 years we have been studying the role of Rho GTPases in epithelial remodeling and morphogenesis in Drosophila. Our accumulated results indicate that in remodeling epithelia Rho1 and Cdc42 influence each other's activity to regulate AJ remodeling and cell tension, whereas in a proliferating epithelium the Cdc42 polarity complex regulates apoptosis induced compensatory proliferation by modulating Rho1 activity. We will now identify candidates mediating Rho1 and Cdc42 crosstalk and determine how they do so. We shall use both drosophila genetics and molecular and cellular biological approaches in drosophila or mammalian cell lines. In addition to surface cadherins, cytosolic proteins are recruited to forming AJ. These proteins couple cadherin adhesion to activities that modulate the cytoskeleton or cell survival/proliferation. The Ajuba family of LIM domain containing adapter or scaffolding proteins are such proteins. As with Rho GTPases, our efforts, over the past 3 years, determining their role in mammalian epithelial morphogenesis, in vivo, has been challenging due to overlapping tissue expression and functional redundancy of family members. Drosophila has a single gene, djub. We have shown that djub is an essential gene and a novel regulator of epithelial organ size as a component of the Hippo signaling pathway. We will now determine how Ajuba LIM proteins regulate the Hippo signaling pathway in mammals and drosophila, to influence epithelial tissue growth.