Application of Rho antagonist to neuronal cell bodies promotes neurite growth in compartmented cultures and regeneration of retinal ganglion cell axons in the optic nerve of adult rats.
Inactivation of Rho promotes neurite growth on inhibitory substrates and axon regeneration in vivo. Here, we compared axon growth when neuronal cell bodies or injured axons were treated with a cell-permeable Rho antagonist (C3-07) in vitro and in vivo. In neurons plated in compartmented cultures, application of C3-07 to either cell bodies or distal axons promoted axonal growth on myelin-associated glycoprotein substrates. In vivo, an injection of C3-07 into the eye promoted regeneration of retinal ganglion cell (RGC) axons in the optic nerve after microcrush lesion. Delayed application of C3-07 promoted RGC growth across the lesion scar. Application of C3-07 completely prevented RGC cell death for 1 week after axotomy. To investigate the mechanism by which Rho inactivation promotes RGC growth, we studied slow axonal transport. Reduction in slow transport of cytoskeletal proteins was observed after axotomy, but inactivation of Rho did not increase slow axonal transport rates. Together, our results indicate that application of a Rho antagonist at the cell body is neuroprotective and overcomes growth inhibition but does not fully prime RGCs for active growth.
Bertrand
Johanne
J
Département de Pathologie et biologie cellulaire, Université de Montréal, Montréal, Québec, Canada, H3T 1J4.
Winton
Matthew J
MJ
Rodriguez-Hernandez
Nieves
N
Campenot
Robert B
RB
McKerracher
Lisa
L
D036002:ADP Ribose Transferases / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured / Q000187:drug effects; D002921:Cicatrix / Q000473:pathology; D003470:Culture Media; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D007267:Injections; D008866:Microsurgery; D018992:Myelin-Associated Glycoprotein; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000502:physiology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D009900:Optic Nerve / Q000187:drug effects / Q000502:physiology*; D020221:Optic Nerve Injuries / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology; D017783:Superior Cervical Ganglion / Q000166:cytology; D014822:Vitreous Body; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology
D003470:Culture Media; D003598:Cytoskeletal Proteins; D018992:Myelin-Associated Glycoprotein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D036002:ADP Ribose Transferases; C503499:C0-05 ADP-ribosyltransferase; C503498:C3-07 ADP-ribosyltransferase; D020741:rho GTP-Binding Proteins