HEDGEHOG SIGNALING IN DEVELOPMENT AND DISEASE

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DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the mechanisms of long-distance cell signaling that are important to development and to disease. We address these important issues with a model system, applying its powerful genetic and molecular techniques to identify and analyze key genes and processes. Our work has shown that in Drosophila, the hedgehog (hh) gene plays a central role setting up and regulating both the segments in the embryo and the compartment borders and signaling centers in the wing disc. Our recent work has focused on the activities of its receptor, Patched (Ptc) and on the transcription factor that mediates Hh signal transduction, Cubitus interruptus (Ci). The human orthologs of both Ptc and Ci have been implicated in a number of human diseases, including cancer. Specific aims are proposed in this application to: (1) complete a forward genetic screen to identify additional components of the Hh signal transduction pathway; (2) identify novel targets of Hh signal transduction using complementary molecular approaches; (3) characterize the structure and regulation of the Patched receptor; (4) analyze the conversion of Ci to its repressor and activator forms; and (5) describe the mechanism by which Hh moves from its sites of synthesis to engage its receptor in neighboring or a distant cells.