2025
Sciencw

Epithelial polarization by the planar cell polarity complex is exclusively non–cell autonomous

Authors:

Lena P. Basta, Bradley W. Joyce, Eszter Posfai, Danelle Devenport

Keywords:

Epithelial polarization; planar cell polarity; Celsr1

Abstract:

Introduction: Planar cell polarity (PCP) is an essential property of tissues in which subcellular protrusions or polarized behaviors coordinately align across a tissue plane. Mutations in PCP cause severe developmental defects in vertebrates and are strongly linked to birth defects in humans. The PCP pathway consists of two opposing membrane-associated protein complexes that asymmetrically localize to opposite sides of cell interfaces, bridged by the atypical cadherin Celsr1. How PCP complexes organize into asymmetric distributions that align across entire tissues is not well understood but is thought to involve a global orienting cue together with feedback interactions between the PCP components that polarize their distributions both within and between cells.

Rationale: Despite the inherently multicellular nature of PCP, it is not known how many cells are required for PCP proteins to asymmetrically segregate to opposite sides of the cell. Can polarity arise intrinsically within individual cells, or are interactions between neighboring cells absolutely required? We have directly addressed this question in the murine epidermis by generating chimeric mouse embryos consisting of dual PCP-reporter (Fz6-3xGFP; tdTomato-Vangl2) cells mixed with unlabeled cells that lack the PCP cadherin Celsr1. Through visualizing opposing Fz6 and Vangl2 PCP complexes simultaneously in single cells, cell pairs, and small multicellular clusters surrounded by Celsr1 mutant cells that are unable to form intercellular PCP bridges, we tested the requirement for intercellular PCP interactions to partition Fz6 and Vangl2. Notably, this chimeric epidermal system preserves global tissue-level polarity cues and epidermal architecture.

Results: We found that opposing PCP complexes do not asymmetrically segregate in individual cells that cannot form PCP bridges with their neighbors (single cell). Rather, a single Celsr1 homotypic interface between two cells was both necessary and sufficient for sorting of PCP components to opposite sides of the junction (cell pair). Cells with two Celsr1 homotypic interfaces established cellular-level asymmetry, in which both junctions polarized with opposing PCP complexes aligned in the same orientation (cell triplet). The orientation of junctional polarity in cells with one or two Celsr1 interfaces did not always align with the global tissue axes.

Conclusion: Our findings indicate that cell-autonomous feedback interactions are insufficient to generate polarity and that Celsr1 homotypic binding in trans initiates the feedback interactions that lead to asymmetric sorting of opposing PCP complexes. Furthermore, the self-organizing interactions that polarize PCP components can override directional signals from relatively weak global cues.