Sarm1 is not necessary for activation of neuron-intrinsic growth programs yet required for the Schwann cell repair response and peripheral nerve regeneration.

Upon peripheral nervous system (PNS) injury, severed axons undergo rapid SARM1-dependent Wallerian degeneration (WD). In mammals, the role of SARM1 in PNS regeneration, however, is unknown. Here we demonstrate that is not required for axotomy induced activation of neuron-intrinsic growth programs and axonal growth into a nerve crush site. However, in the distal nerve, is necessary for the timely induction of the Schwann cell (SC) repair response, nerve inflammation, myelin clearance, and regeneration of sensory and motor axons. In mice, regenerated fibers exhibit reduced axon caliber, defective nerve conduction, and recovery of motor function is delayed. The growth hostile environment of distal nerve tissue was demonstrated by grafting of nerve into WT recipients. SC lineage tracing in injured WT and mice revealed morphological differences. In the distal nerve, the appearance of p75+, c-Jun+ SCs is significantly delayed. , p75 and c-Jun upregulation in nerves can be rescued by pharmacological inhibition of ErbB kinase. Together, our studies show that is not necessary for the activation of neuron intrinsic growth programs but in the distal nerve is required for the orchestration of cellular programs that underlie rapid axon extension.