This proposal aims to investigate the role of the Planar Cell Polarity pathway in regulating epithelial homeostasis and cancer progression. The skin is a fundamental human organ that is continually shedding and making new cells and hairs. Adult stem cells orchestrate this cycle of self renew via a complex set of molecular signals. Understanding precisely what these signals do to the cells is an extremely active area of research. One signaling pathway that remains unexplored during skin homeostasis is the Planar Cell Polarity Pathway (PCP). All multicellular organisms exhibit some degree of polarity, and use conserved sets of genes to establish it. Two such conserved genes are Vangl1 and Vangl2, members of the PCP pathway. These genes can regulate a variety of cellular outputs from migration to the production of stereocillia. Both Vangl1 and Vangl2 are expressed in the adult epidermis. This proposal will define the precise epidermal compartments that express each gene. It will also explore the function of these genes during normal skin activity by knocking-out the genes in mice. The effect on the cells will be explored, from changes in the differentiation state of the stem cells to altered expression or localization patterns of adhesion molecules. Different mechanisms are likely employed for the production of new skin cells versus the production of a new hair. Cancer is a major health concern worldwide and one of the most brutal killers of all human diseases. Understanding the molecular switch from a normal to a cancer cell, the mechanisms that allow metastasis, and the precise causes of death by these aberrant cells are essential to finding a cure. The Vangl genes have recently been implicated in metastatic cancers. The Watt lab has a number of tumor models that will facilitate the study of Vangl genes during skin cancer progression. Changes in localization or activity of these genes may promote metastasis via increased migration or loss of adhesion. These possibilities will be explored. PUBLIC HEALTH RELEVANCE: The aim of this grant is to explore the basic biology of skin and hair self- renewal. These processes may be disrupted in skin related disease such as psoriasis, alopecia and chronic ulcers. This grant will also investigate the mechanisms underlying the causes of skin cancer metastasis.