(Verbatim) Many key intercellular signals required for hair follicle morphogenesis in the embryo and cyclical hair growth in the adult remain unidentified at the molecular level. It is already well established that inappropriate activation of follicular intercellular signaling pathways can cause tumors and hair loss. Therefore identification of the signaling molecules and receptors that operate in hair follicles will provide us with a better understanding of the molecular events underlying pathogenic states in the skin and may ultimately permit the development of novel therapies. Published data and our Preliminary Studies suggest specific WNT proteins as strong candidates for several of these signals. The goals of this proposal are to test the hypothesis that WNT proteins convey information between follicular epithelial cells and between the follicular epithelium and the mesenchyme, and that this dialog is required for the normal development and function of hair follicles. To test this hypothesis we will: (1) Define the profile of WNT receptor (Frizzled) gene expression in developing and mature hair follicles; (2) Determine the effects of blocking interactions between WNT proteins and their Frizzled receptors in the epidermis in vivo; (3) Determine the effects on skin and hair development of loss of function mutations in two Wnt genes that are expressed at key stages in hair follicle development and hair growth; and (4) Determine the roles of WNT signaling in the dermal component of the hair follicle by creating a null mutation in an essential effector of WNT signaling, specifically within this compartment. Understanding the roles of these key signaling molecules in developing and mature skin will provide us with new insight into normal skin and hair follicle biology and disease states including hair loss diseases and skin cancers.
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