Inactivation of Rho signaling pathway promotes CNS axon regeneration.
Regeneration in the CNS is blocked by many different growth inhibitory proteins. To foster regeneration, we have investigated a strategy to block the neuronal response to growth inhibitory signals. Here, we report that injured axons regrow directly on complex inhibitory substrates when Rho GTPase is inactivated. Treatment of PC12 cells with C3 enzyme to inactivate Rho and transfection with dominant negative Rho allowed neurite growth on inhibitory substrates. Primary retinal neurons treated with C3 extended neurites on myelin-associated glycoprotein and myelin substrates. To explore regeneration in vivo, we crushed optic nerves of adult rat. After C3 treatment, numerous cut axons traversed the lesion to regrow in the distal white matter of the optic nerve. These results indicate that targeting signaling mechanisms converging to Rho stimulates axon regeneration on inhibitory CNS substrates.
Lehmann
M
M
Département de Pathologie et Biologie Cellulaire, Université de Montréal, Succursale Centreville, Montréal, Québec H3C 3J7, Canada.
Fournier
A
A
Selles-Navarro
I
I
Dergham
P
P
Sebok
A
A
Leclerc
N
N
Tigyi
G
G
McKerracher
L
L
D036002:ADP Ribose Transferases / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D001905:Botulinum Toxins; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D016501:Neurites / Q000502:physiology*; D009900:Optic Nerve / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D012160:Retina / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D020690:GTPase-Activating Proteins; D018992:Myelin-Associated Glycoprotein; C085379:rho GTPase-activating protein; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins