PTEN deletion enhances the regenerative ability of adult corticospinal neurons.
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.
Liu
Kai
K
F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
Lu
Yi
Y
Lee
Jae K
JK
Samara
Ramsey
R
Willenberg
Rafer
R
Sears-Kraxberger
Ilse
I
Tedeschi
Andrea
A
Park
Kevin Kyungsuk
KK
Jin
Duo
D
Cai
Bin
B
Xu
Bengang
B
Connolly
Lauren
L
Steward
Oswald
O
Zheng
Binhai
B
He
Zhigang
Z
D000375:Aging / Q000502:physiology; D000818:Animals; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D002574:Cervical Vertebrae; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008526:Medulla Oblongata / Q000502:physiology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011712:Pyramidal Tracts / Q000502:physiology* / Q000503:physiopathology / Q000648:ultrastructure; D013003:Somatosensory Cortex / Q000502:physiology / Q000503:physiopathology; D013116:Spinal Cord / Q000502:physiology / Q000503:physiopathology / Q000648:ultrastructure; D013119:Spinal Cord Injuries / Q000503:physiopathology; D013569:Synapses / Q000502:physiology / Q000648:ultrastructure; D058570:TOR Serine-Threonine Kinases; D013904:Thoracic Vertebrae
D047908:Intracellular Signaling Peptides and Proteins; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse