Mitotic Regulation of planar cell polarity in the mammalian epidermis

Abstract

During cell division, polarized epithelial cells employ mechanisms to preserve cell polarity and tissue integrity. In dividing cells of the mammalian skin, planar cell polarity (PCP) is maintained through the bulk internalization, equal segregation, and polarized recycling of cortical PCP proteins. The dramatic redistribution of PCP proteins coincides precisely with cell cycle progression, but the mechanisms coordinating PCP and mitosis are unknown. Here we identify Plk1 as the key regulator linking PCP dynamics with mitotic progression. Plk1 interacts with core PCP component, Celsr1, via a conserved polo-box domain (PBD) binding motif, localizes to mitotic endosomes and directly phosphorylates Celsr1. Plk1-dependent phosphorylation activates the endocytic motif specifically during mitosis, allowing bulk recruitment of Celsr1 into endosomes. Inhibiting Plk1 activity blocks PCP internalization and perturbs PCP asymmetry. Mimicking dileucine motif phosphorylation is sufficient to drive Celsr1 internalization during interphase. Following internalization, PCP vesicles are retained in the cytoplasm until the completion of mitosis. Inhibiting Plk1 after initial internalization has occurred causes cells to arrest in mitosis and leads to premature Celsr1 vesicle recycling, suggesting that Plk1 also has additional roles in mediating endosome retention. Inducing early cell cycle exit by inhibiting Cdk1 causes early endosome return to the membrane. Together, these results demonstrate that endosome recycling is coupled with cell cycle exit. This thesis provides an overview of how polarity can be maintained in the context of regenerative tissues that need to transmit and preserve global tissue organization while undergoing dramatic cellular changes that accompanies mitotic progression.