Sticking together: How adherens junctions orchestrate epithelial integrity

Abstract

Epithelial tissues form regulated barriers that separate the outside world from the internal environment, and come in various forms to enable their organ-specific functions. All these intricate epithelial topologies need to be properly arranged during embryonic development and maintained throughout life. Epithelia hereto rely on adherens junctions that connect cells and act as key guardians of epithelial organization and integrity. In this thesis we investigate, across different scales, how regulatory mechanisms and functions of cadherin-based adhesions orchestrate epithelial architecture. Firstly, we describe a novel role for β-catenin in the supramolecular organization of adherens junctions. We find that condensation of β-catenin through its intrinsically disordered regions drives clustering of the cadherin complex, and that this clustering promotes the formation of de novo adherens junctions between epithelial cells. Secondly, we delineate the molecular response of adherens junctions to forces during mitosis. We uncover that to withstand elevated forces that arise from the rounding of mitotic cells, cadherin adhesions between the mitotic cell and its neighbors are reinforced through recruitment of the actin-binding protein vinculin. This mechanoresponse selectively occurs in neighbors of mitotic cells, and the resulting asymmetry in composition of the mitotic cadherin complex allows for the morphological rearrangements of cell rounding while maintaining epithelial integrity. Thirdly, we describe how the role of adherens junctions in epithelial architecture extends beyond its adhesive function. We review the potential mechanisms that drive the dissemination of E-cadherin-deficient cells from the gastric epithelium, which represents the initiating step of diffuse-type gastric cancer. We subsequently experimentally determine that this stems from the mispositioning of dividing cells due to the loss of E-cadherin-dependent planar cell divisions. Taken together, this thesis advances our understanding of adherens junctions in epithelial architecture, offering insights into their regulatory mechanisms at several levels.