THE NOTCH SIGNALING PATHWAY: STRUCTURE AND MECHANISM

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DESCRIPTION (provided by applicant): The long-term goal of this project is a detailed understanding of how intercellular signals control cell fate during animal development. Cell-cell signaling via the Notch (N) receptor is a principal mechanism for assigning cell fates in a broad variety of developmental processes in metazoans, including neurogenesis. Though the N signaling pathway has been studied extensively, many essential elements of its structure and operation remain mysterious or poorly understood. We have identified a novel group of genes in Drosophila that we refer to as the Bearded (Brd) family, after the founding member. These genes all encode small proteins with a strongly basic amphipathic a helical domain. Brd family genes are integral, core members of the N pathway in Drosophila. They are expressed specifically at multiple sites of N signaling in both embryonic; and post-embryonic development, and are directly regulated by the N-activated transcription factor Suppressor of Hairless. When overexpressed, they are potent modulators of N signaling activity. Initial loss-of-function genetic studies indicate that Brd family proteins act as effectors of N signaling in both nervous system and muscle development. Clearly, a mechanistic understanding of N pathway function in arthropods will require elucidating the developmental role and biochemical mode of action of the Brd protein family. The research program described in this application is designed to achieve this goal, and has 3 specific aims: (1) Genetic analysis of Brd family gene and protein function. (2) Ceil biological and molecular analysis of Brd family protein expression and localization. (3) Identification and analysis of Brd family protein partners and interactions. We expect that our investigation will greatly enlarge our knowledge of how an ancient cell-ceil signaling pathway specifies cell fate, and may offer insight into the pathogenesis of N pathway disease syndromes such as Alagille and CADASIL.