Long-range chemical signalling in vivo is regulated by mechanical signals.

Biological processes are regulated by chemical and mechanical signals, yet how these signalling modalities interact remains poorly understood. Here we identify a crosstalk between tissue stiffness and long-range chemical signalling in the developing Xenopus laevis brain. Targeted knockdown of the mechanosensitive ion channel Piezo1 in retinal ganglion cells or in the brain tissue surrounding retinal ganglion cells causes pathfinding errors in vivo. In the brain parenchyma, Piezo1 downregulation decreases the expression of the diffusive long-range chemical guidance cues Semaphorin3A (Sema3A) and Slit1, which instruct turning responses in distant cells. Furthermore, Piezo1 knockdown results in tissue softening due to reduced expression of the adhesion proteins NCAM1 and N-cadherin. Targeted depletion of NCAM1 and N-cadherin similarly reduces tissue stiffness and Sema3A expression. Conversely, increasing environmental stiffness ex vivo enhances tissue-level force generation and Slit1 and Sema3A expression. Finally, in vivo stiffening of soft brain regions induces ectopic Sema3A production via a Piezo1-dependent mechanism. Overall, these findings demonstrate that tissue mechanics locally modulates the availability of diffusive, long-range chemical signals, thus influencing cell function at sites distant from the mechanical cue.