Regulation of Planar Cell Polarity by Protein tyrosine kinase 7 in the mammalian Auditory Sensory Epithelium

Planar cell polarity (PCP) is a common feature of all tissues, and refers to the coordinated orientation of cells and/or cellular structures in an axis parallel to the plane of a tissue. Diverse morphogenetic and physiological processes depend on the proper establishment of PCP. In vertebrates, the genetic factors that regulate PCP include the conserved core PCP pathway genes and ciliary genes. In addition, the elucidation of a number of distinct PCP components suggests that vertebrates have adapted additional mechanisms to control PCP in diverse cellular processes. Our lab has previously identified Protein tyrosine kinase 7 (Ptk7), encoding an atypical receptor tyrosine kinase, as a novel vertebrate-specific regulator of PCP. The underlying mechanisms by which Ptk7 regulates PCP are poorly understood. The clear morphological manifestations of PCP in the mouse auditory sensory epithelium or organ of Corti (OC) make it a powerful model system to study PCP signaling in mammals. In the OC, PCP is defined by the V-shaped structure of the stereociliary bundle that sits atop each sensory hair cell and by the uniform orientation of stereociliary bundles across the epithelium. The precise establishment of these features is critical for the proper hearing functions of the cochlea. The goal of this dissertation was to dissect the cellular and molecular mechanisms by which Ptk7 regulates PCP in the OC. We have discovered that Ptk7 functions in parallel with the noncanonical Wnt/PCP pathway to regulate actomyosin contractility and orient hair cell PCP. For the first time, we demonstrate an active role for nonsensory supporting cells in hair cell PCP where an apical contractile myosin II network assembles and is proposed to exert polarized contractile tension on hair cells. We also determined a pathway for actomyosin regulation in the OC where Ptk7 promotes planar polarized Src signaling at cell-cell contacts to spatially regulate actomyosin contractility. These studies have led us to propose a new model for PCP regulation in the OC where Ptk7 mediates anisotropic myosin II based contractile tension between hair cell and supporting cell contacts to orient hair cell PCP. Together, my work provides novel mechanistic insights into hair cell PCP regulation.