A conserved Arf-GEF modulates axonal integrity through RAB-35 by altering neuron-epidermal attachment

Neurites of sensory neurons densely innervate the skin and are embedded within it. These delicate structures are exposed to acute and chronic mechanical strain and yet their integrity is maintained throughout life. Although evidence suggests a neuroprotective role for the skin, the molecular pathways involved are still poorly understood. In C. elegans, the cytoskeletal molecule UNC-70/{beta}-spectrin functions in synergy with the small GTPase RAB-35 within the skin to stabilize neuron-epidermal attachment structures against mechanical strain and prevent movement-induced damage to mechanosensitive axons. However, the full suite of molecules regulating these specialized attachments remains elusive. Here, through an unbiased forward genetic screen we have identified a guanine nucleotide exchange factor (GEF) previously associated with the endocytic-recycling machinery, AGEF-1a, that impacts axonal maintenance. We show that AGEF-1a functions selectively within the skin to regulate the integrity of the embedded axons. Mechanistically, we reveal that this effect is achieved through an interaction between AGEF-1a and epidermal RAB-35 to facilitate its activation, which in turn modulates the neuron-epidermal attachments. Finally, we demonstrate that the function of this GEF is highly conserved, with the expression of its human ortholog, BIG2 capable of replacing AGEF-1a. Together, we reveal the specific molecular machinery responsible for fine-tuning neuron-epidermal attachments and maintaining axonal integrity during life.