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
-
mTOR protein, mouse
-
Protein Serine-Threonine Kinases
-
TOR Serine-Threonine Kinases
-
PTEN Phosphohydrolase
-
Pten protein, mouse