Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo

Abstract

Collective cell migration (CCM) is essential for morphogenesis, tissue remodelling, and cancer invasion 1, 2. In vivo, groups of cells move in an orchestrated way through tissues. This movement requires forces and involves mechanical as well as molecular interactions between cells and their environment. While the role of molecular signals in CCM is comparatively well understood 1, 2, how tissue mechanics influence CCM in vivo remains unknown. Here we investigated the importance of mechanical cues in the collective migration of the Xenopus laevis neural crest cells, an embryonic cell population whose migratory behaviour has been likened to cancer invasion 3. We found that, during morphogenesis, the head mesoderm underlying the cephalic neural crest stiffens. This stiffening initiated an epithelial-to-mesenchymal transition (EMT) in neural crest cells and triggered their collective migration. To detect changes in their mechanical environment, neural crest use integrin/vinculin/talin-mediated mechanosensing. By performing mechanical and molecular manipulations, we showed that mesoderm stiffening is necessary and sufficient to trigger neural crest migration. Finally, we demonstrated that convergent extension of the mesoderm, which starts during gastrulation, leads to increased mesoderm stiffness by increasing the cell density underneath the neural crest. These results unveil a novel role for mesodermal convergent extension as a mechanical coordinator of morphogenesis, and thus reveal a new link between two apparently unconnected processes, gastrulation and neural crest migration, via changes in tissue mechanics. Overall, we provide the first demonstration that changes in substrate stiffness can trigger CCM by promoting EMT in vivo. More broadly, our results raise the exciting idea that tissue mechanics combines with molecular effectors to coordinate morphogenesis 4.