Effects of PTEN and Nogo Codeletion on Corticospinal Axon Sprouting and Regeneration in Mice

J Neurosci. 2015 Apr 22;35(16):6413-28. doi: 10.1523/JNEUROSCI.4013-14.2015.


Axons in the adult CNS have poor ability to grow after injury, impeding functional recovery in patients of spinal cord injury. This has been attributed to both a developmental decline in neuron-intrinsic growth ability and the presence of extrinsic growth inhibitors. We previously showed that genetic deletion of Nogo, an extrinsic inhibitor, promoted axonal sprouting from uninjured corticospinal tract (CST) neurons but not regeneration from injured CST neurons, whereas genetic deletion of PTEN, an intrinsic inhibitor, promoted both CST sprouting and regeneration. Here we test the hypothesis that combining an elevation of neuron-intrinsic growth ability and a reduction of extrinsic growth inhibition by genetic codeletion of PTEN and Nogo may further improve injury-induced axonal growth. In an apparent paradox, additionally deleting Nogo further enhanced CST regeneration but not sprouting in PTEN-deleted mice. Enhanced CST regeneration and sprouting in PTEN and PTEN/Nogo-deleted mice were associated with no or only temporary improvement in functional recovery. Our data illustrate that neuron-intrinsic and -extrinsic factors regulate axon regeneration and sprouting in complex ways and provide proof-of-principle evidence that targeting both can further improve regeneration. Neuron-intrinsic growth ability is an important determinant of neuronal responsiveness to changes in extrinsic growth inhibition, such that an elevated intrinsic growth state is a prerequisite for reducing extrinsic inhibition to take effect on CST regeneration. Meanwhile, additional strategies are required to unleash the full potential for functional recovery with enhanced axon regeneration and/or sprouting.

Keywords: CNS repair; axon regeneration; axon sprouting; extrinsic growth inhibition; neuron-intrinsic growth ability; spinal cord injury.

Publication types

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

MeSH terms

  • Animals
  • Axons / physiology*
  • Behavior, Animal / physiology
  • Mice
  • Mice, Mutant Strains
  • Myelin Proteins / deficiency*
  • Myelin Proteins / genetics
  • Myelin Proteins / physiology
  • Nerve Regeneration / genetics
  • Nerve Regeneration / physiology*
  • Nogo Proteins
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / physiology
  • Pyramidal Tracts / physiology*
  • Recovery of Function / genetics
  • Recovery of Function / physiology
  • Spinal Cord Injuries / physiopathology


  • Myelin Proteins
  • Nogo Proteins
  • Rtn4 protein, mouse
  • PTEN Phosphohydrolase
  • Pten protein, mouse