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

Biological processes are regulated by chemical and mechanical signals, yet the interaction between these signalling modalities remains poorly understood. Using the developing Xenopus laevis brain as a model system, we identified a critical crosstalk between tissue stiffness and long-range chemical signalling in vivo . Targeted knockdown of the mechanosensitive ion channel Piezo1 in retinal ganglion cells (RGCs) led to pathfinding errors in vivo. However, pathfinding errors were also observed in RGCs expressing Piezo1, when Piezo1 was downregulated in the surrounding brain tissue. Depleting Piezo1 in the brain parenchyma led to a decrease in the expression of the long-range chemical guidance cues Semaphorin3A (Sema3A) and Slit1, which instruct turning responses in distant cells. Furthermore, Piezo1 knockdown markedly reduced tissue stiffness. This tissue softening was independent of Sema3A depletion, and was caused by a decrease in the cell-cell adhesion proteins NCAM1 and N-Cadherin. Downregulating NCAM1 and N-Cadherin was sufficient to reduce tissue stiffness and Sema3A expression. Conversely, increasing environmental stiffness ex vivo resulted in enhanced tissue-level force generation and an increase in Slit1 and Sema3A expression. Moreover, stiffening soft brain regions in vivo induced ectopic Sema3A production via a Piezo1-dependent mechanism. Hence, tissue mechanics can locally modulate the availability of diffusive, long-range chemical signals, thus influencing cell function at sites distant from the mechanical cue. Such indirect regulatory mechanisms of cell function through mechanical signals are likely widespread across biological systems.