Role of Wnt and Noggin in development and Cancer

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DESCRIPTION (provided by applicant): Epithelial bud development is the first step in the formation of lung, limb, teeth and hair. To form a bud from a single layer of epithelium, cells must utilize their cytoskeleton in conjunction with cell-cell and cell-substratum connections to remodel their interactions with neighboring cells. Of major importance in defining cell shape, polarity and migration is the actin cytoskeleton and its associations with E-cadherin-mediated cell-cell junctions (adherens junctions) and b1 integrin-mediated cell substratum junctions (focal adhesions). Precisely how these junctions utilize actin filaments to accomplish this remodeling is unknown. However, when the process of epithelial bud formation goes astray, disastrous results can include not only malformation of physical structures but also malignancies. Mice will be used as a source of cultured epithelial stem cells and their skin used as models to characterize the Wnt and noggin mediated changes in a) actin dynamics, cell adhesion and migration, and b) gene transcription, at the early stages of hair follicle bud development. The long-term goal is to understand how various signaling pathways converge to regulate follicular morphogenesis and how misregulation leads to cancer.