Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse

Neuroscience. 2017 Feb 20;343:372-383. doi: 10.1016/j.neuroscience.2016.12.020. Epub 2016 Dec 21.

Abstract

Adult mammalian CNS axons generally do not regenerate, creating an obstacle to effective repair and recovery after neuronal injury. The canonical Wnt/β-catenin signaling pathway is an essential signal transduction cascade that regulates axon growth and neurite extension in the developing mammalian embryo. In this study, we investigated whether a Wnt/β-catenin signaling activator could be repurposed to induce regeneration in the adult CNS after axonal injury. We used a retinal ganglion cell (RGC) axon crush injury model in a transgenic Wnt reporter mouse, and intravitreal injections were used to deliver Wnt3a or saline to the RGC cell bodies within the retina. Our findings demonstrated that Wnt3a induced Wnt signaling in RGCs and resulted in significant axonal regrowth past the lesion site when measured at two and four weeks post-injury. Furthermore, Wnt3a-injected eyes showed increased survival of RGCs and significantly higher pattern electroretinography (PERG) amplitudes compared to the control. Additionally, Wnt3a-induced axonal regeneration and RGC survival were associated with elevated activation of the transcription factor Stat3, and reducing expression of Stat3 using a conditional Stat3 knock-out mouse line led to diminished Wnt3a-dependent axonal regeneration and RGC survival. Therefore, these findings reveal a novel role for retinal Wnt signaling in axonal regrowth and RGC survival following axonal injury, which may lead to the development of novel therapies for axonal regeneration.

Keywords: Stat3; Tcf-LacZ​ mice.; Wnt signaling; intravitreal injection; optic nerve crush; optic nerve regeneration; retina.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axons / metabolism*
  • Axons / pathology
  • Cell Survival / physiology
  • Disease Models, Animal
  • Female
  • Male
  • Mice, Inbred C3H
  • Mice, Transgenic
  • Microglia / metabolism
  • Microglia / pathology
  • Nerve Regeneration / physiology*
  • Neuronal Outgrowth / physiology
  • Neuroprotection / physiology
  • Optic Nerve Injuries / metabolism*
  • Optic Nerve Injuries / pathology
  • Random Allocation
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / metabolism
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / pathology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Wnt Signaling Pathway / physiology*
  • Wnt3A Protein / administration & dosage
  • Wnt3A Protein / genetics
  • Wnt3A Protein / metabolism

Substances

  • Recombinant Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Wnt3A Protein