Abstract
It is known that neuronal growth cones control the advance of axons in part by sensing and responding to the substrate rigidity, yet the mechanical interactions governing these mechanisms are unclear. We recently measured traction force in Aplysia Californica growth cones as it developed over time in response to a new adhesion substrate. We found that the level of substrate deformation, rather than the level of traction force generated, better predicts whether the growth cone would advance towards the adhesion site or not. Our observations support a hypothesis that actin-based adhesion complexes, which can undergo micron-scale elastic deformation, regulate the coupling between the retrogradely flowing actin cytoskeleton and the substrate, stimulating growth cone advance if sufficiently abundant. This hypothesis is further supported in the current work through mathematical modeling to stochastically simulate the behavior of the growth cone as it encounters a substrate with a specific stiffness. In particular, the model simulates the behavior of the micrometer-scale elastic adhesion structures as they form a dynamic linkage between the retrograde F-actin flow and the adhesion substrate, which ultimately slow down the flow enough to trigger a growth cone advance response. As such the stochastic model predicts the time required for the growth cone to respond given a specific substrate stiffness. The model reproduces our previous experimental observations in which traction force gradually increased during adhesion-mediated growth cone advance.Simulation results show that the time to trigger a growth cone advance response and the number of adhesion structures required increase with increasing stiffness. Both experimental results and theoretical simulations support the hypothesis that sensing and responding to environmental stiffness in neuronal growth cones is mediated by micrometer-scale actin-based elastic structures.
Published Version
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