遺伝子改変胚性幹細胞由来胚における、哺乳類神経管閉鎖に必要なビンキュリン依存的な力応答の解明

Epithelial sheets build complex structures by converting mechanical forces into changes in cell and tissue organization. During neural tube closure, the neural plate dynamically remodels to produce a closed tube that provides the structural foundation for the developing brain and spinal cord. How cells maintain epithelial integrity despite the forces required for tissue morphogenesis during neural tube closure is not understood. We show that mechanical forces are upregulated during cranial neural tube closure in the mouse embryo and recruit the force-sensitive protein Vinculin to adherens junctions. Leveraging a genetically engineered embryonic stem cell-based pipeline to efficiently generate mutant embryos, we show that Vinculin mutants produce mechanical forces correctly but fail to maintain cell adhesion under tension, resulting in a failure of cranial neural fold elevation. Live imaging of cell behavior in the developing midbrain reveals that apical constriction, cell rearrangement, and cell division initiate correctly in Vinculin mutants, but their progression is impeded by disruption of adherens junctions at sites of increased tension. These results demonstrate that Vinculin is required to reinforce cell adhesion in response to increasing physiological forces during cranial neural tube closure, and that this activity is necessary to translate these forces into changes in tissue structure.