The multiscale mechanics of axon durotaxis

During neurodevelopment, neuronal axons navigate through the extracellular environment,
guided by various cues to establish connections with distant target cells. Among other factors,
axon trajectories are influenced by heterogeneities in environmental stiffness, a process known
as durotaxis, the guidance by substrate stiffness gradients. Here, we develop a three-scale model
for axonal durotaxis. At the molecular scale, we characterise the mechanical interaction between
the axonal growth cone cytoskeleton, based on molecular-clutch-type interactions dependent on
substrate stiffness. At the growth cone scale, we spatially integrate this relationship to obtain a
model for the traction generated by the entire growth cone. Finally, at the cell scale, we model
the axon as a morphoelastic filament growing on an adhesive substrate, and subject to durotactic growth cone traction. Firstly, the model predicts that, depending on the local substrate
stiffness, axons may exhibit positive or negative durotaxis, and we show that this key property
entails the existence of attractive zones of preferential stiffness in the substrate domain. Second, we show that axons will exhibit reflective and refractive behaviour across interface between
regions of different stiffness, a basic process which may serve in the deflection of axons. Lastly,
we test our model in a biological scenario wherein durotaxis was previously identified as a possible guidance mechanism in vivo. Overall, this work provides a general mechanistic theory for
exploring complex effects in axonal mechanotaxis and guidance in general.