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

Abstract

AbstractUpon 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 thatSarm1is not required for axotomy induced activation of neuron-intrinsic growth programs and axonal growth into a nerve crush site. However, in the distal nerve,Sarm1is necessary for the timely induction of the Schwann cell (SC) repair response, nerve inflammation, myelin clearance, and regeneration of sensory and motor axons. InSarm1-/-mice, regenerated fibers exhibit reduced axon caliber, defective nerve conduction, and recovery of motor function is delayed. The growth hostile environment ofSarm1-/-distal nerve tissue was demonstrated by grafting ofSarm1-/-nerve into WT recipients. SC lineage tracing in injured WT andSarm1-/-mice revealed morphological differences. In theSarm1-/-distal nerve, the appearance of p75NTR+, c-Jun+ SCs is significantly delayed.Ex vivo, p75NTRand c-Jun upregulation inSarm1-/-nerves can be rescued by pharmacological inhibition of ErbB kinase. Together, our studies show thatSarm1is 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.