Deletion of murine Sarm1 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 Sarm1 in PNS regeneration remains unclear. We show that in mouse dorsal root ganglia with their axons cut, Sarm1 delayed the activation of injury-induced transcriptional programs associated with axon outgrowth and immune function. After sciatic nerve crush in Sarm1^-/- 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 Sarm1^-/- 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 Sarm1^-/- nerves into wild-type mice and mouse wild-type nerves into Sarm1^-/- mice revealed that the Sarm1^-/- nerve microenvironment was hostile to wild-type axon regeneration and, conversely, that Sarm1^-/- axons robustly grew into mouse wild-type nerve grafts. Ex vivo, the appearance of c-Jun-labeled Schwann cells in cultured mouse Sarm1^-/- nerves was delayed but could be accelerated by pharmacological inhibition of ErbB kinase. Our study highlights the opposing functions of Sarm1 deficiency in dorsal root ganglia and distal nerves in mice, the consequence of which is delayed PNS regeneration.