BETA CATENIN SIGNALING DURING FEATHER TRACT DEVELOPMENT

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A problem central to the generation of organs and organisms is the allocation of multipotent cells to different fates in appropriate positions and numbers. The interactions between intercellular signaling pathways which contribute to this process appear to be common to the generation of many embryonic structures. The feather field is well suited to study the early steps of pattern formation because the large and accessible fields of cells competent to participate in this process are amenable to manipulation both in vivo and in vitro. Feather buds are precisely patterned structures whose morphogenesis is mediated by co-ordinated activity of epithelial and mesenchymal signaling centers. Buds are positioned relative to each other in a precise array and any perturbation in the formation or activity of the signaling centers that organize the bud is readily detected as an interruption in the regularity of that array. The long term goal of this project is to employ the feather tract to dissect the interactions between signaling pathways that generate pattern in organs generated by epithelial mesenchymal interactions. The roles of several signaling molecules, including BMPs, FGFs and Notch and its ligands, have been partially elucidated. Recent work has demonstrated that activation of the beta-catenin signaling pathway is a crucial step in initiation of bud formation. This proposal focuses on the mechanisms by which activation of this pathway is localized during tract development. The effects of blocking this signaling pathway will be assessed to refine observations based on gain of function experiments. Members of the Wnt family can activate beta-catenin signaling, so their expression and activity during tract formation will be explored. The effects of retroviruses employed to alter the expression and activity of Wnts at different times and positions in the tract in ovo will be assessed at the morphological and molecular levels. The sequential roles of the beta-catenin pathway and the Wnts that activate it that are inferred from in vivo work will be tested in a series of in vitro experiments targeted to specific steps of tract development. Spatial or temporal differences in response to exogenous Wnts will be used to infer the interaction between this and other signaling pathways, and the roles of different TCFs and Grgs in modulating responsiveness to Wnts to pattern the tract will be investigated. This should enhance our understanding of the formation of many organs as well as suggest strategies to control the developmental defects and cancer that are caused by deregulated activity of the beta-catenin signaling pathway.