Epithelial Folding Irreversibility is Controlled by Elastoplastic Transition via Mechanosensitive Actin Bracket Formation

Abstract

During morphogenesis, epithelial sheets undergo sequential folding to form three-dimensional organ structures. The resulting folds are irreversible, ensuring that morphogenesis progresses in one direction. However, the mechanism establishing the irreversibility of folding remains unclear. Here, we report a novel mechanical property of epithelia that is responsible for folding irreversibility. Using a newly developed mechanical indentation assay, we demonstrate that short-term or low-curvature folding induces an elastic, shape-restoring response. In contrast, combined long-term, high-curvature folding results in plastic, irreversible deformation. This elastic-to-plastic transition occurs in a switch-like manner, with critical thresholds for the folding curvature and duration. Specific cells at the fold initiate this transition, sensing the curvature and duration of folding on their apical side via mechanosensitive signaling pathways, including transient receptor potential canonical (TRPC) 3/6-mediated calcium influx and ligand-independent epidermal growth factor receptor activation. These pathways induce F-actin accumulation into a bracket-like structure across the fold, establishing the transition. The duration threshold is determined and tunable by the actin polymerization rate. These results demonstrate that cells control the irreversibility of epithelial folding by detecting folding characteristics and adaptively switching between elastic and plastic responses. This finding resolves a long-standing question about the directionality of morphogenesis.