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

Neurites of sensory neurons innervate the skin and are embedded within it. These delicate structures are chronically exposed to mechanical strain and yet their integrity is maintained throughout life. In C. elegans, UNC-70 (a β-spectrin protein) functions in synergy with the small GTPase RAB-35 within the skin to stabilize neuron-epidermal attachment against mechanical strain and prevent movement-induced damage to mechanosensitive axons. However, the molecular pathway regulating these specialized attachments remains elusive. Here, through an unbiased genetic screen, we have identified a guanine nucleotide exchange factor (GEF), AGEF-1, that impacts axonal maintenance. This molecule is known to function in endocytic recycling and its human ortholog, BIG2 (also known as ARFGEF2), is associated with the development of the periventricular nodular heterotopia. We show that AGEF-1 functions selectively within the skin to regulate axonal integrity of mechanosensitive neurons. Mechanistically, we reveal that AGEF-1 binds to epidermal RAB-35 and regulates its activity, modulating neuron-epidermal attachment stability. Finally, we demonstrate that this GEF is highly conserved, with its human ortholog BIG2 being capable of replacing AGEF-1. Together, we reveal the molecular machinery responsible for fine-tuning neuron-epidermal attachments and maintaining axonal integrity during life.