Elasto-Plastic Transition in Epithelial Folding

Abstract

AbstractDuring morphogenesis, epithelial sheets fold sequentially to make up three-dimensional organ structures. The resulting fold is irreversible, thereby allowing morphogenesis to proceed unidirectionally. However, how the irreversibility of folding is established remains unclear. We report a novel mechanical property of epithelia that is responsible for folding irreversibility. In ex vivoandin vitrocultures, epithelia exhibit an elastic response and restore their original shapes when folding is induced by short-term mechanical indentation. In contrast, long-term indentation induces a plastic response, resulting in irreversible deformation. Remarkably, the transition from an elastic to a plastic response occurs in a switch-like manner with a critical duration. This transition is established by the accumulation of F-actin into a bracket-like structure across the fold, with the critical duration determined and tunable by the actin polymerization rate. Bracket formation and the resulting transition require two mechanosensing pathways: TRPC3/6-mediated calcium influx and ligand-independent epidermal growth factor receptor (EGFR) activation. While each pathway is independently triggered by deformation, calcium influx specifically occurs at the fold under EGFR activation. These results demonstrated that cells control epithelial folding irreversibility by detecting the temporal characteristics of deformation and adaptively switching between elastic and plastic responses. This finding, thus, resolves a long-standing question concerning the directionality of morphogenesis.