DESCRIPTION (provided by applicant): Loss of cell polarity and invasive behavior are regarded as hallmarks of cancer, but surprisingly little is known about the mechanisms that preserve cell polarity during tissue growth and turnover. Polarity refers to the asymmetric partitioning of membrane components and subcellular structures, is oriented along both apicobasal and planar axes, and is essential for the proper assembly and function of epithelial tissues. The preservation of cell polarity is of crucial importance in tumor suppression and therefore, special mechanisms must exist to preserve polarity when cells divide. Consistent with this notion, we previously discovered a novel and unexpected mechanism that preserves planar polarity in dividing cells of the skin epidermis. More recent data demonstrate this mechanism is controlled directly by mitotic kinases, the same machinery that controls cell cycle progression and is deregulated in cancer. This is the first demonstration that cell division and planar cell polarity are controlled by the same regulatory machinery, and may explain why, in cancer, hyperproliferation and cellular disorder are so closely intertwined. We hypothesize that the cell cycle machinery regulates cell polarity to ensure its preservation when cells divide, and that aberrations uncoupling polarity from cell cycle control will impair tissue architecture and proliferative homeostasis. Using a multifaceted approach combining mammalian genetics with cell biology, proteomics, and time-lapse imaging we will address our hypothesis in the context of epidermal development and regeneration. Specifically we will 1) define the cell cycle- dependent events that regulate planar cell polarity throughout mitotic progression; 2) determine how the landscape of proliferation across the epidermis impacts global planar cell polarity, and 3) decipher how perturbations in planar cell polarity influence proliferation and differentiation durig skin development and homeostasis. Successful completion of the proposed experiments will bring a shift in our understanding of how tissue architecture and growth are connected where it is recognized that proliferation and cell polarity are connected by the same machinery. Understanding the mechanisms that mediate crosstalk between these two essential cell biological processes will help us to reevaluate current therapies that target cell cycle machinery in light of their effects on cell and tissue polarity.