Neuron-epidermal attachment protects hyper-fragile axons from mechanical strain.

Axons experience significant strain caused by organismal development and movement. A combination of intrinsic mechanical resistance and external shielding by surrounding tissues prevents axonal damage, although the precise mechanisms are unknown. Here, we reveal a neuroprotective function of neuron-epidermal attachment in Caenorhabditis elegans. We show that a gain-of-function mutation in the epidermal hemidesmosome component LET-805/myotactin, in combination with a loss-of-function mutation in UNC-70/ß-spectrin, disrupts the uniform attachment and subsequent embedment of sensory axons within the epidermis during development. This generates regions of high tension within axons, leading to spontaneous axonal breaks and degeneration. Completely preventing attachment, by disrupting HIM-4/hemicentin or MEC-5/collagen, eliminates tension and alleviates damage. Finally, we demonstrate that progressive neuron-epidermal attachment via LET-805/myotactin is induced by the axon during development, as well as during regeneration after injury. Together, these results reveal that establishment of uniform neuron-epidermal attachment is critical to protect axons from mechanical strain during development.