Celsr1 adhesive interactions mediate the asymmetric organization of planar polarity complexes.

Abstract

To orchestrate collective polarization across tissues, planar cell polarity (PCP) proteins localize asymmetrically to cell junctions, a conserved feature of PCP that requires the atypical cadherin Celsr1. We report that mouse Celsr1 engages in both <i>trans</i>- and <i>cis</i>-interactions, and organizes into dense and highly stable punctate assemblies. We provide evidence suggesting that PCP-mutant variant of Celsr1, Celsr1^Crsh, selectively impairs lateral <i>cis</i>-interactions. Although Celsr1^Crsh mediates cell adhesion in trans, it displays increased mobility, diminishes junctional enrichment, and fails to engage in homophilic adhesion with the wild-type protein, phenotypes that can be rescued by ectopic <i>cis</i>-dimerization. Using biochemical and super-resolution microscopy approaches, we show that although Celsr1^Crsh physically interacts with PCP proteins Frizzled6 and Vangl2, it fails to organize these proteins into asymmetric junctional complexes. Our results suggest mammalian Celsr1 functions not only as a <i>trans</i>-adhesive homodimeric bridge, but also as an organizer of intercellular Frizzled6 and Vangl2 asymmetry through lateral, <i>cis</i>-interactions.