329 Regulation of planar cell polarity via Celsr1 adhesion during development and disease

Planar cell polarity (PCP) refers to the collective polarization of cells along a tissue plane, such as ordered alignment body hairs in skin. Disruption PCP leads developmental disorders heart, neural tube, inner ear and A hallmark feature is asymmetric localization core proteins Fz6 Vangl2 at an intercellular junctional complex organized by cadherin family member Celsr1. Our studies Celsr1 mouse revealed that functions not only trans-adhesive molecular bridge, but also organizer asymmetry junctions through lateral, cis-interactions dimerization. These reveal key roles for adhesion vertebrate development. Interestingly, mutations occur patients with epidermal-derived tumors carcinomas malignant melanomas, defects spina bifida congenital heart defects. We hypothesized these perturb establishment function impairing adhesion. To test this possibility, WT various mutants was assessed using combination assays, advanced optical imaging, vivo murine genetic approaches. identified repeats were defective determined ability accumulate cell-cell borders form stable adhesive interactions fluorescence recovery after photobleaching. melanoma result variants display significantly reduced function. In addition loss-of-function mutants, we human gain-of-function activity. Overall, our findings indicate organize coordinate suggest signaling are altered both skin cancers.