Collective cell migration is essential for morphogenesis, tissue remodelling and cancer invasion1,2. In vivo, groups of cells move in an orchestrated way through tissues. This movement involves mechanical as well as molecular interactions between cells and their environment. While the role of molecular signals in collective cell migration is comparatively well understood1,2, how tissue mechanics influence collective cell migration 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 invasion3. We found that, during morphogenesis, the head mesoderm underlying the cephalic neural crest stiffens. This stiffening initiates an epithelial-to-mesenchymal transition in neural crest cells and triggers their collective migration. To detect changes in their mechanical environment, neural crest cells use mechanosensation mediated by the integrin–vinculin–talin complex. By performing mechanical and molecular manipulations, we show that mesoderm stiffening is necessary and sufficient to trigger neural crest migration. Finally, we demonstrate 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 show that convergent extension of the mesoderm has a role as a mechanical coordinator of morphogenesis, and reveal a link between two apparently unconnected processes—gastrulation and neural crest migration—via changes in tissue mechanics. Overall, we demonstrate that changes in substrate stiffness can trigger collective cell migration by promoting epithelial-to-mesenchymal transition in vivo. More broadly, our results raise the idea that tissue mechanics combines with molecular effectors to coordinate morphogenesis4.
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We thank A. J. Thompson for assistance with the AFM. This study was supported by grants to R.M. from the Medical Research Council (J000655), Biotechnology and Biological Sciences Research Council (M008517) and Wellcome Trust; to K.F. from the Medical Research Council (Career Development Award G1100312/1) and from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (R21HD080585); to G.C. from the European Research Council (Consolidator grant MolCellTissMech, agreement 647186); and by postdoctoral fellowships to E.H.B. from EMBO (LTF-971) and Marie Skłodowska Curie (IF-2014_ST VivoMechCollMigra, agreement 658536). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Extended data figures
Chemotaxis assay testing the collective response of non- and pre-migratory neural crest clusters towards Sdf-1 on glass
Neural crest labelled with nuclear (magenta) and membrane (cyan) markers. Note that both populations directionally migrate towards Sdf-1. Time-lapse setting was 1 picture every 5 min; 49 frames are shown; 20x objective.
Chemotaxis assay testing the collective response of neural crest clusters to Sdf-1 on substrates of varying stiffness
Neural crest labelled with nuclear (magenta) and membrane (cyan) markers. Note that cells migrating on soft gels do not migrate towards Sdf-1. Time-lapse setting was 1 picture every 5 min; 50 frames are shown; 63x water-immersion objective.
Confocal time-lapse of neural crest clusters migrating toward Sdf-1 on substrates of varying stiffness
Neural crest labelled with nuclear (magenta) and membrane (cyan) markers. Sdf-1 located to the right side of the NC. Note the lack of polarity in cells plated on soft gels. Time-lapse setting was 1 picture every 16 seconds; 29 frames are shown; 63x objective.
Neural crest labelled with nuclear (magenta) and membrane (cyan) markers. Notice that cells migrating on soft gels do not disperse. Time-lapse setting was 1 picture every 5 min; 250 frames are shown; 20x objective.