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

Biological processes are regulated by chemical signals (e.g., morphogens, growth factors, and guidance cues) and mechanical signals (e.g., tissue stiffness and cellular forces). Yet, the interaction between these two signals in vivo remains poorly understood. Using the developing Xenopus laevis brain as a model system, where growing retinal ganglion cell (RGC) axons are guided by both chemical and mechanical cues, we demonstrate that knockdown of the mechanosensitive ion channel, Piezo1, exerts cell-intrinsic and cell-extrinsic effects on axon pathfinding. Targeted Piezo1 knockdown in 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 levels led to both a decrease in the expression of the long-range chemical guidance cues, Semaphorin3A (Sema3A) and Slit1, and a decrease in tissue stiffness. While tissue softening was independent of Sema3A depletion, Slit1 and Sema3A expression increased significantly in stiffer environments in vitro. Moreover, stiffening soft brain regions in vivo induced ectopic production of Sema3A, via a Piezo1-dependent mechanism. Our results show that brain tissue mechanics modulates the expression of key chemical cues. This dynamic interplay between tissue mechanics and long-range chemical signalling likely extends across diverse biological systems throughout development, homeostasis, and disease.