An epidermal membrane-associated periodic skeleton restricts endocytosis to stabilize neuron-epidermal attachment and preserve axons

Spectrins are highly conserved molecules that form a distinct membrane-associated periodic scaffold within axons to provide mechanical resilience. In <i>Caenorhabditis elegans</i>, UNC-70/ß-Spectrin also functions within the epidermis to maintain the integrity of sensory neurons. The precise molecular organization in this tissue and the cellular mechanisms that mediate this protection are unknown. Here, using three-dimensional structured illumination microscopy, we show that epidermal SPC-1/α-Spectrin and UNC-70/ß-Spectrin form a crescent-shaped scaffold with a periodicity of ~200 nm that embraces adjacent axons. This epidermal Spectrin scaffold is induced by developing axons and reformed during axonal regeneration, creating a "molecular imprint" of the nervous system. Disruption of this epidermal scaffold causes axonal damage, and we propose that it protects axons by restricting the endocytosis of cell adhesion molecules required for axonal-epidermal adhesion. Our findings reveal a distinct periodic Spectrin scaffold within the epidermis that is molded by the developing nervous system and protects axons from damage.