GSK3-CRMP2 signaling mediates axonal regeneration induced by Pten knockout

Commun Biol. 2019 Aug 23;2:318. doi: 10.1038/s42003-019-0524-1. eCollection 2019.

Abstract

Knockout of phosphatase and tensin homolog (PTEN-/-) is neuroprotective and promotes axon regeneration in mature neurons. Elevation of mTOR activity in injured neurons has been proposed as the primary underlying mechanism. Here we demonstrate that PTEN-/- also abrogates the inhibitory activity of GSK3 on collapsin response mediator protein 2 (CRMP2) in retinal ganglion cell (RGC) axons. Moreover, maintenance of GSK3 activity in Gsk3 S/A knockin mice significantly compromised PTEN-/--mediated optic nerve regeneration as well as the activity of CRMP2, and to a lesser extent, mTOR. These GSK3S/A mediated negative effects on regeneration were rescued by viral expression of constitutively active CRMP2T/A, despite decreased mTOR activation. Gsk3 S/A knockin or CRMP2 inhibition also decreased PTEN-/- mediated neurite growth of RGCs in culture and disinhibition towards CNS myelin. Thus, the GSK3/CRMP2 pathway is essential for PTEN-/- mediated axon regeneration. These new mechanistic insights may help to find novel strategies to promote axon regeneration.

Keywords: Brain injuries; Cellular neuroscience; Regeneration and repair in the nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Female
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice, Knockout
  • Nerve Regeneration*
  • Nerve Tissue Proteins / metabolism*
  • Neurites / metabolism
  • Optic Nerve / metabolism
  • Optic Nerve / pathology
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / metabolism*
  • Phosphorylation
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • collapsin response mediator protein-2
  • TOR Serine-Threonine Kinases
  • Glycogen Synthase Kinase 3
  • PTEN Phosphohydrolase