Spectrin forms a periodic cytoskeleton within the epidermis to preserve axonal integrity

Spectrins are highly conserved molecules that form a distinct membrane associated periodic scaffold within axons thought to provide mechanical resilience. In C. elegans , UNC-70/ß-Spectrin also functions outside the nervous system, within the epidermis, to maintain the integrity of sensory neurons. The precise molecular organization and cellular mechanisms that mediate this protection are unknown. Here, using 3D-structured illumination microscopy, we show that within the epidermis spectrins 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, and creates a “molecular imprint” of the adjacent nervous system. Disruption of this epidermal scaffold causes widespread axonal damage in sensory and motor neurons. These findings reveal the existence of a distinct and periodic spectrin framework within the epidermis that is molded by the developing nervous system and is necessary to protect it from mechanical damage.