PTEN deletion enhances the regenerative ability of adult corticospinal neurons

Nat Neurosci. 2010 Sep;13(9):1075-81. doi: 10.1038/nn.2603. Epub 2010 Aug 8.

Abstract

Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.

Publication types

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

MeSH terms

  • Aging / physiology
  • Animals
  • Axons / physiology
  • Axons / ultrastructure
  • Cervical Vertebrae
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Medulla Oblongata / physiology
  • Medulla Oblongata / physiopathology
  • Mice
  • Mice, Transgenic
  • Nerve Regeneration / physiology*
  • Neurons / physiology*
  • Neurons / ultrastructure
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyramidal Tracts / physiology*
  • Pyramidal Tracts / physiopathology
  • Pyramidal Tracts / ultrastructure
  • Somatosensory Cortex / physiology
  • Somatosensory Cortex / physiopathology
  • Spinal Cord / physiology
  • Spinal Cord / physiopathology
  • Spinal Cord / ultrastructure
  • Spinal Cord Injuries / physiopathology
  • Synapses / physiology
  • Synapses / ultrastructure
  • TOR Serine-Threonine Kinases
  • Thoracic Vertebrae

Substances

  • Intracellular Signaling Peptides and Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • Pten protein, mouse