Microtubule deacetylation enables in vivo collective cell migration by tuning cell stiffness in relation to substrate stiffness*

Cells in multicellular organisms migrate during tissue formation, regeneration, and immune defense. Cells migrate in vivo by exerting forces on surrounding tissue structures with cell-substrate mechanical interaction shown to be important in cell migration. By combining computational modeling and in vivo experimental data from Xenopus laevis embryos we show that neural crest cell stiffness is dynamically reduced in response to the temporal stiffening of the mesoderm -  the substrate upon which neural crest cells move in vivo. We discover that the reduction in neural crest cell stiffness and consequently its migration is triggered by microtubule deacetylation mediated by Piezo1. We show that the effect of microtubule deacetylation on cell movement is well characterized by the stiffness ratio between the substrate(sub) and the cell (E_sub/E_cell). As lowering microtubule acetylation and consequently cell stiffness rescues cell migration in soft substrates, we provide evidence that an optimal cell-to-substrate stiffness ratio is important in allowing for collective cell migration rather than a fixed value of substrate stiffness.