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Misguidance and modulation of axonal regeneration by Stat3 and Rho/ROCK signaling in the transparent optic nerve

V Pernet1, S Joly, N Jordi

  • 1Brain Research Institute, University of Zürich and Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland. pernet@hifo.uzh.ch

Cell Death & Disease
|July 23, 2013
PubMed

Insights

Stat3 activation promotes axonal regeneration after CNS injury. However, this process is hindered by axonal misguidance, which can be corrected to improve long-distance regeneration.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Regenerative Medicine

Background:

  • The visual system provides a model for studying molecular mechanisms of axonal regeneration in the central nervous system (CNS) after injury.
  • Ciliary neurotrophic factor (CNTF) is a potent neurotrophic factor for axonal regeneration in the injured optic nerve.

Purpose of the Study:

  • To investigate the role of Signal transducer and activator of transcription 3 (Stat3) in axonal regeneration and neuronal survival following optic nerve crush.
  • To analyze the effects of Stat3 activation on axonal guidance and regeneration in the injured CNS.

Main Methods:

  • Adult mice underwent optic nerve crush injury.
  • Retinal ganglion cells were infected with adeno-associated virus serotype 2 (AAV2) carrying wild-type (Stat3-wt) or constitutively active (Stat3-ca) Stat3 cDNA.
  • Axonal regeneration was analyzed in 3D whole-mounted optic nerves after tissue clearing.
  • Pharmacological blockade of Rho-associated kinase (ROCK) was employed.
  • Sustained delivery of CNTF was used as a comparative model.

Main Results:

  • AAV2-mediated Stat3 activation (Stat3-wt and Stat3-ca) promoted axonal regeneration in the injured optic nerve.
  • Stat3-ca stimulation led to axons with irregular trajectories, including frequent U-turns, indicating guidance deficits.
  • ROCK inhibition reduced axonal U-turns and enhanced Stat3-ca-induced regeneration.
  • Similar beneficial effects on regeneration were observed with sustained CNTF delivery.

Conclusions:

  • Stat3 plays a crucial role in activating the neuronal growth program essential for CNS regeneration.
  • Axonal misguidance is a significant impediment to long-distance regeneration and target re-innervation after CNS trauma.
  • Correcting axonal misguidance can improve long-distance axon regeneration in the injured adult CNS.

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