Cell-size-dependent regulation of Ezrin dictates epithelial resilience to stretch by countering myosin-II-mediated contractility

The epithelial adaptations to mechanical stress are facilitated by molecular and tissue-scale changes that include the strengthening of junctions, cytoskeletal reorganization, and cell-proliferation-mediated changes in tissue rheology. However, the role of cell size in controlling these properties remains underexplored. Our experiments in the zebrafish embryonic epidermis, guided by theoretical estimations, reveal a link between epithelial mechanics and cell size, demonstrating that an increase in cell size compromises the tissue fracture strength and compliance. We show that an increase in E-cadherin levels in the proliferation-deficient epidermis restores epidermal compliance but not the fracture strength, which is largely regulated by Ezrin—an apical membrane-cytoskeleton crosslinker. We show that Ezrin fortifies the epithelium in a cell-size-dependent manner by countering non-muscle myosin-II-mediated contractility. This work uncovers the importance of cell size maintenance in regulating the mechanical properties of the epithelium and fostering protection against future mechanical stresses. [Display omitted] •Cell size contributes to mechanical properties of the epithelial tissue•Cell size impacts the epithelial compliance in an adhesion-dependent manner•Apical Ezrin levels are inversely correlated with the epithelial cell size•Ezrin offsets myosin-mediated contractility to maintain the tissue stiffness Chouhan et al. unravel a mechanistic link between cell size and tissue mechanics in epithelia. They show that increased cell size increases epithelial compliance in an E-cadherin-dependent manner. They further uncover the importance of Ezrin and E-cadherin in offsetting actomyosin contractility in epithelial cells to regulate tissue fracture strength.