Environmental Elasticity Regulates Cell-type Specific RHOA Signaling and Neuritogenesis of Human Neurons

The microenvironment of developing neurons is a dynamic landscape of both chemical and mechanical cues that regulate cell proliferation, differentiation, migration, and axon extension. While the regulatory roles of chemical ligands in neuronal morphogenesis have been described, little is known about how mechanical forces influence neurite development. Here, we tested how substratum elasticity regulates neurite development of human forebrain (hFB) neurons and human motor neurons (hMNs), two populations of neurons that naturally extend axons into distinct elastic environments. Using polyacrylamide and collagen hydrogels of varying compliance, we find that hMNs preferred rigid conditions that approximate the elasticity of muscle, whereas hFB neurons preferred softer conditions that approximate brain tissue elasticity. More stable leading-edge protrusions, increased peripheral adhesions, and elevated RHOA signaling of hMN growth cones contributed to faster neurite outgrowth on rigid substrata. Our data suggest that RHOA balances contractile and adhesive forces in response to substratum elasticity. [Display omitted] •Motor neurons derived from hiPSCs are tuned to grow optimally on rigid substrata•hiPSCs derived forebrain neurons prefer softer substrata•RHOA-dependent adhesion contributes to elasticity preferences•Modulating RHOA affects axon development depending on substrata elasticity Axons extend through varying tissue elasticities in vivo, but it is unknown how tissue mechanics influence neuron development. In this article, Gómez and colleagues examine how substratum elasticity affects process formation by human motor and forebrain neurons. They show that motor neurons extend axons best on more rigid conditions compared with forebrain neurons, which is due to differences in RHOA-mediated adhesion.