Cell cycle control of cell polarity and fate in epidermal morphogenesis

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Loss of cell polarity and invasive behavior are hallmarks of cancer, but how cell polarity is preserved during tissue growth and turnover is poorly understood. 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. We have shown that to preserve tissue architecture, epithelial polarity is dynamically remodeled when cells divide. Asymmetrically localized polarity proteins are temporarily removed from the cell surface via bulk endocytosis into the cytoplasm. After division, they are recycled to the surface where polarity is restored. This mechanism is controlled directly by mitotic kinases, the same machinery that controls cell cycle progression and is deregulated in cancer. Thus, 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. In this proposal we build and expand on this foundational work to investigate how cell polarity is restored after mitosis and how cell division facilitates the establishment of robust and aligned tissue polarity. We will capitalize on our recent technical advancements in live and super-resolution imaging of the skin to 1) decipher the transport mechanisms that restore polarity following mitosis and how mitotic repolarization establishes tissue-scale polarity; 2) define the spatial cues that direct mitotic repolarization; and 3) determine how neighboring cells coordinate mitotic removal of intercellular junctions via transendocytosis. Successful completion of ours aims will uncover the mechanisms by which a highly proliferative epithelium preserves tissue integrity.