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

Autor: Schmitd LB; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor MI, USA., Hafner H; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor MI, USA., Ward A; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor MI, USA.; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor MI, USA., Asghari Adib E; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA., Biscola NP; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Kohen R; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor MI, USA., Patel M; Department of Biology, Ball State University, Muncie IN, USA., Williamson RE; Department of Biology, Ball State University, Muncie IN, USA., Desai E; Department of Biology, Ball State University, Muncie IN, USA., Bennett J; Department of Biology, Ball State University, Muncie IN, USA., Saxman G; Department of Biology, Ball State University, Muncie IN, USA., Athaiya M; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor MI, USA., Wilborn D; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor MI, USA., Shumpert J; Department of Biology, Ball State University, Muncie IN, USA., Zhao XF; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor MI, USA., Kawaguchi R; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Geschwind DH; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA, USA., Hoke A; Department of Neurology, The Johns Hopkins University, Baltimore, MD, USA., Shrager P; Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA., Collins CA; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.; Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA., Havton LA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; James J Peters VA Medical Center, Bronx, NY, USA., Kalinski AL; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor MI, USA.; Department of Biology, Ball State University, Muncie IN, USA., Giger RJ; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor MI, USA.; Department of Neurology, University of Michigan Medical School, Ann Arbor MI, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Apr 17. Date of Electronic Publication: 2024 Apr 17.
DOI: 10.1101/2024.03.04.583374
Abstrakt: 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 Sarm1 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, Sarm1 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 Sarm1-/- mice, regenerated fibers exhibit reduced axon caliber, defective nerve conduction, and recovery of motor function is delayed. The growth hostile environment of Sarm1-/- distal nerve tissue was demonstrated by grafting of Sarm1-/- nerve into WT recipients. SC lineage tracing in injured WT and Sarm1-/- mice revealed morphological differences. In the Sarm1-/- distal nerve, the appearance of p75 NTR +, c-Jun+ SCs is significantly delayed. Ex vivo , p75 NTR and c-Jun upregulation in Sarm1-/- nerves can be rescued by pharmacological inhibition of ErbB kinase. Together, our studies show that Sarm1 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.
Databáze: MEDLINE