Abstract

During nervous system development, growing neurons respond to mechanical as well as chemical signals in their environment. How these different signals interact, to guide neurons to their end target, is currently poorly understood. We found that retinal ganglion cell axons grow along stiffness gradients in the developing Xenopus brain. Mechanosensitive ion channels (MSCs) are key players in transducing these mechanical cues into intracellular signals. Pharmacological blocking of MSCs and knockdown of the MSC , Piezo1, caused severe pathfinding errors in vivo. In addition to directly impacting axon growth, downregulation of Piezo1 also dramatically altered the expression of semaphorin3A (Sema3A), a chemical guidance cue known to be critical in axon pathfinding. While Piezo1 knockdown softened brain tissue, knockdown of Sema3A did not alter brain mechanics. Sema3A-producing neuroepithelial cells grown on substrates of varying stiffness adapted expression levels of Sema3A to their mechanical environment. Our results thus indicate that the expression of signalling molecules may be modulated by tissue mechanics, which has important implications given that tissue stiffness changes throughout development as well as during ageing and disease.