The multiscale mechanics of axon durotaxis

TL;DR

This paper presents a comprehensive multiscale model of axon durotaxis, elucidating how axons respond to substrate stiffness gradients during neurodevelopment, with predictions of attraction, repulsion, and deflection behaviors based on local mechanical cues.

Contribution

It introduces a novel three-scale mechanistic model linking molecular interactions, growth cone traction, and axonal growth to substrate stiffness, advancing understanding of axonal guidance mechanisms.

Findings

Axons can exhibit positive or negative durotaxis depending on local stiffness.

Axons demonstrate reflective and refractive behaviors at stiffness interfaces.

The model aligns with in vivo observations of durotactic guidance in neural development.

Abstract

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.