Induction of Corticospinal Regeneration by Lentiviral trkB-induced Erk Activation

Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7215-20. doi: 10.1073/pnas.0810624106. Epub 2009 Apr 9.

Abstract

Several experimental manipulations of the CNS environment successfully elicit regeneration of sensory and bulbospinal motor axons but fail to elicit regeneration of corticospinal axons, suggesting that cell-intrinsic mechanisms limit the regeneration of this critical class of motor neurons. We hypothesized that enhancement of intrinsic neuronal growth mechanisms would enable adult corticospinal motor axon regeneration. Lentiviral vectors were used to overexpress the BDNF receptor trkB in layer V corticospinal motor neurons. After subcortical axotomy, trkB transduction induced corticospinal axon regeneration into subcortical lesion sites expressing BDNF. In the absence of trkB overexpression, no regeneration occurred. Selective deletion of canonical, trkB-mediated neurite outgrowth signaling by mutation of the Shc/FRS-2 activation domain prohibited Erk activation and eliminated regeneration. These findings support the hypothesis that the refractory regenerative state of adult corticospinal axons can be attributed at least in part to neuron-intrinsic mechanisms, and that activation of ERK signaling can elicit corticospinal tract regeneration.

Publication types

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

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression Regulation
  • Lentivirus / genetics*
  • Nerve Regeneration*
  • Neurites / drug effects
  • Neurites / metabolism
  • PC12 Cells
  • Phosphotyrosine / metabolism
  • Rats
  • Receptor, trkB / genetics
  • Receptor, trkB / metabolism*
  • Spinal Cord / physiology*

Substances

  • Brain-Derived Neurotrophic Factor
  • Phosphotyrosine
  • Receptor, trkB
  • Extracellular Signal-Regulated MAP Kinases