Cell-cell communication is essential to the development and function of the skin and its appendages. We discovered that the canonical WNT/beta-catenin intercellular signaling pathway is required for initiating the formation of all types of hair follicle placodes during embryogenesis, and is essential postnatally for hair growth. These findings have potential significance for the development of strategies for regenerating hair follicles in cases of congenital absence or loss, and for the treatment of hair growth disorders. However, as activating mutations in beta-catenin can cause hair follicle tumors, it will be of critical importance to delineate the precise mechanisms by which WNT/beta-catenin signals normally initiate hair follicle development and regulate postnatal hair growth, and to identify the WNT ligands that control normal development and growth. To these ends we will test the hypothesis that WNT/beta-catenin signaling initiates hair follicle morphogenesis by direct activation of genes of the tumor necrosis factor (TNF) and TNF receptor familes. We will manipulate WNT/beta-catenin signaling in inducible transgenic mouse models to determine the requirement for this pathway for the onset and maintenance of the anagen phase of the hair growth cycle, and we will examine the skin phenotypes of mice mutant for two hair follicle-expressed Wnt genes. Unexpectedly, we discovered that expression of Frizzled WNT receptors in developing and postnatal skin is not confined to sites of known activity of the WNT/beta-catenin pathway, suggesting that WNT signaling through alternate pathways may contribute to the development and maintenance of the skin and hair follicles. Non-canonical WNT signaling regulates the planar cell polarity of epithelial cells and cell movements in vertebrate embryos. We will test the hypothesis that non-canonical WNT signaling is important for cell movements and polarity in skin epithelia by depleting the function of a key non-canonical WNT signaling pathway component in mouse skin in vivo and in cultured keratinocyes.
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