External mechanical force drives axonal cytoskeletal rearrangements.

Axons experience strong mechanical forces due to animal movement. These forces serve as sensory cues in mechanosensory neurons, but their impact on other neuron types remains poorly defined. Here, we uncover an axonal response to external physiological forces that plays a key role in axon integrity. Using cell-specific degradation alleles and chemogenetic silencing, we find that Talin, RhoA, and non-muscle myosin II function in a C. elegans motor neuron axon in response to forces generated by muscle contraction. In control animals, this response promotes cytoskeletal continuity by regulating the local oscillatory behavior of individual microtubule polymers. When the structural integrity of the axon is compromised by disrupting the spectrin-based membrane-associated skeleton, excessive RhoA activity promotes axon breakage. This phenotype is accompanied by mislocalized F-actin and myosin and conversion of local microtubule oscillations to robust movements that generate large cytoskeletal discontinuities. Importantly, reducing the mechanical force on the axon or degrading neuronal RhoA restores cytoskeletal continuity and prevents axon breakage in spectrin mutants. These results uncover an axonal mechanism that controls cytoskeletal continuity and axon integrity in response to external mechanical forces.