Hyperactivated Stat3 boosts axon regeneration in the CNS

Exp Neurol. 2016 Jun;280:115-20. doi: 10.1016/j.expneurol.2016.03.004. Epub 2016 Apr 6.

Abstract

Axonal regeneration after spinal cord injury (SCI) is intrinsically and extrinsically inhibited by multiple factors. One major factor contributing to intrinsic regeneration failure is the inability of mature neurons in the central nervous system (CNS) to activate regeneration-associated transcription factors (TFs) post-injury. A prior study identified TFs overexpressed in neurons of the peripheral nervous system (PNS) compared to the CNS; some of these could be involved in the ability of PNS neurons to regenerate. Of these, signal transducer and activator of transcription 3 (STAT3), as well its downstream regeneration-associated targets, showed a significant upregulation in PNS neurons relative to CNS neurons, and a constitutively active variant of Stat3 (Stat3CA) promoted neurite growth when expressed in cerebellar neurons (Lerch et al., 2012; Smith et al., 2011). To further enhance STAT3's neurite outgrowth enhancing activity, Stat3CA was fused with a viral activation domain (VP16). VP16 hyperactivates TFs by recruiting transcriptional co-factors to the DNA binding domain (Hirai et al., 2010). Overexpression of this VP16-Stat3CA chimera in primary cortical neurons led to a significant increase of neurite outgrowth as well as Stat3 transcriptional activity in vitro. Furthermore, in vivo transduction of retinal ganglion cells (RGCs) with AAV constructs expressing VP16-Stat3CA resulted in regeneration of optic nerve axons after injury, to a greater degree than for those expressing Stat3CA alone. These findings confirm and extend the concept that overexpression of hyperactivated transcription factors identified as functioning in PNS regeneration can promote axon regeneration in the CNS.

Keywords: Activation domain; Axon regeneration; Neurite outgrowth; Optic nerve; Transcription factor; VP16.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Axons / physiology
  • Cells, Cultured
  • Central Nervous System / pathology*
  • Cerebral Cortex / cytology
  • Cholera Toxin / toxicity
  • Female
  • Herpes Simplex Virus Protein Vmw65 / genetics
  • Herpes Simplex Virus Protein Vmw65 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Nerve Regeneration / physiology*
  • Neurites
  • Optic Nerve Injuries / pathology*
  • Rats
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Transduction, Genetic
  • Up-Regulation / genetics

Substances

  • Herpes Simplex Virus Protein Vmw65
  • STAT3 Transcription Factor
  • Cholera Toxin