Deletion of murine <i>Sarm1</i> results in a microenvironment that delays peripheral nerve regeneration after injury.

Abstract

Upon injury to the mammalian peripheral nervous system (PNS), severed axons undergo rapid SARM1-dependent programmed axon death (Wallerian degeneration), but a potential role for <i>Sarm1</i> in PNS regeneration remains unclear. We show that in mouse dorsal root ganglia with their axons cut, <i>Sarm1</i> delayed the activation of injury-induced transcriptional programs associated with axon outgrowth and immune function. After sciatic nerve crush in <i>Sarm1^-/-</i> mice, axons rapidly extended through the nerve injury site, but growth stalled more distally. Slow axon regeneration in the distal nerve was accompanied by delayed induction of the nerve repair response by Schwann cells and delayed clearance of disintegrating myelin. Nerve fibers did regenerate in <i>Sarm1^-/-</i> mice, but regeneration was delayed, and axons exhibited reduced caliber and aberrant target innervation. Tibial nerve action potentials were weaker, and recovery of hind paw function was delayed but ultimately not impaired. Grafting of mouse <i>Sarm1^-/-</i> nerves into wild-type mice and mouse wild-type nerves into <i>Sarm1^-/-</i> mice revealed that the <i>Sarm1^-/-</i> nerve microenvironment was hostile to wild-type axon regeneration and, conversely, that <i>Sarm1^-/-</i> axons robustly grew into mouse wild-type nerve grafts. Ex vivo, the appearance of c-Jun-labeled Schwann cells in cultured mouse <i>Sarm1^-/-</i> nerves was delayed but could be accelerated by pharmacological inhibition of ErbB kinase. Our study highlights the opposing functions of <i>Sarm1</i> deficiency in dorsal root ganglia and distal nerves in mice, the consequence of which is delayed PNS regeneration.