Abstract
During morphogenesis, epithelial sheets undergo sequential folding to form three-dimensional organ structures. The resulting folds are often irreversible, ensuring that morphogenesis progresses in one direction. However, the mechanism establishing folding irreversibility remains unclear. Here, we report a mechanical property of epithelia that determines folding irreversibility. Using a mechanical assay, we demonstrate that long-term, high-curvature folding induces plastic, irreversible deformations, while short-term or low-curvature folding results in an elastic, shape-restoring response. This elastic-plastic transition occurs in a switch-like manner, with critical thresholds in folding curvature and duration. The transition is induced by F-actin accumulating into a bracket-like structure across the fold, triggered by cells sensing deformations via mechanosensitive signaling pathways, including TRPC 3/6-mediated calcium influx and ligand-independent EGFR activation. These results demonstrate that cells control epithelial folding irreversibility by detecting folding characteristics and adaptively switching between elastic and plastic responses, providing mechanical insight into the directionality of morphogenesis.