Sustained GSK3 activity markedly facilitates nerve regeneration

Nat Commun. 2014 Jul 31:5:4561. doi: 10.1038/ncomms5561.

Abstract

Promotion of axonal growth of injured DRG neurons improves the functional recovery associated with peripheral nerve regeneration. Both isoforms of glycogen synthase kinase 3 (GSK3; α and β) are phosphorylated and inactivated via phosphatidylinositide 3-kinase (PI3K)/AKT signalling upon sciatic nerve crush (SNC). However, the role of GSK3 phosphorylation in this context is highly controversial. Here we use knock-in mice expressing GSK3 isoforms resistant to inhibitory PI3K/AKT phosphorylation, and unexpectedly find markedly accelerated axon growth of DRG neurons in culture and in vivo after SNC compared with controls. Moreover, this enhanced regeneration strikingly accelerates functional recovery after SNC. These effects are GSK3 activity dependent and associated with elevated MAP1B phosphorylation. Altogether, our data suggest that PI3K/AKT-mediated inhibitory phosphorylation of GSK3 limits the regenerative outcome after peripheral nerve injury. Therefore, suppression of this internal 'regenerative break' may potentially provide a new perspective for the clinical treatment of nerve injuries.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Gene Expression Regulation
  • Gene Knock-In Techniques
  • Glycogen Synthase Kinase 3 / genetics*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Crush
  • Nerve Regeneration / genetics*
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphatidylinositol 3-Kinase / genetics*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphorylation
  • Primary Cell Culture
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Recovery of Function
  • Sciatic Nerve / injuries*
  • Sciatic Nerve / metabolism
  • Signal Transduction

Substances

  • Protein Isoforms
  • Phosphatidylinositol 3-Kinase
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha