Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway.
The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.
Park
Kevin Kyungsuk
KK
F. M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Liu
Kai
K
Hu
Yang
Y
Smith
Patrice D
PD
Wang
Chen
C
Cai
Bin
B
Xu
Bengang
B
Connolly
Lauren
L
Kramvis
Ioannis
I
Sahin
Mustafa
M
He
Zhigang
Z
D000818:Animals; D001369:Axons / Q000502:physiology*; D019771:Axotomy; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival; D051379:Mice; D018345:Mice, Knockout; D009409:Nerve Crush; D009416:Nerve Regeneration; D009900:Optic Nerve; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D014176:Protein Biosynthesis; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000502:physiology; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D038601:Ribosomal Protein S6; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse