Epithelial morphogenesis is a process fundamental to the development of all animals. Proper shaping of epithelia during development is essential to the normal function of all organs. Inappropriate development and/or homeostasis of epithelial tissue underlies conditions and diseases as diverse as external physical malformation, congenital heart failure, digestive and respiratory ailments, and nee plastic malignancy. Epithelia develop in response to complex signals, however the mechanisms by which these signals are integrated to achieve normal development are poorly understood. Drosophila leg imaginal discs provide a simple and well-characterized model system in which to study epithelial morphogenesis. Major advantages include excellent cell biology and amenability to genetic analysis. Imaginal disc development depends on coordination of signaling activities from the steroid hormone ecdysone and the RhoA signaling pathway. We propose to examine the relationship between the ecdysone response and RhoA signaling in developing leg imaginal discs. The first specific aim tests the hypothesis that the RhoA pathway regulates ecdysone-responsive gene expression and morphogenesis by seeking to impair RhoA signaling during developmental transitions controlled by ecdysone. Effects on ecdysone-dependent gene expression and morphogenesis will be determined. The second specific aim tests the hypothesis Mat the ecdysone responsive Stubble type II transmembrane serine protease regulates RhoA signaling in leg imaginal discs. In order to understand the role for Stubble in RhoA signaling, a yeast two-hybrid soreen will be performed to identify proteins that physically interact with the Stubble protease. The third specific aim seeks to complete cloning and characterization of a gene that interacts genetically with Stubble and RhoA during leg morphogenesis. Cloning of this gene should help us to understand how the complex ecdysone and RhoA pathway signals are integrated to control epithelial morphogenesis.
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