Rho-associated kinase II (ROCKII) limits axonal growth after trauma within the adult mouse spinal cord.
Rho GTPases are thought to mediate the action of several axonal growth inhibitors in the adult brain and spinal cord. RhoA has been targeted pharmacologically in both humans and animals to promote neurite outgrowth and functional recovery following CNS trauma. However, rat spinal cord injury studies suggest a complicated and partial benefit of inhibiting Rho or its downstream effector, Rho-associated kinase (ROCKII). This limited benefit may reflect inhibition of other kinases, poor access, or a minimal role of ROCKII in vivo. Therefore, we studied ROCKII mutant mice to probe this pathway genetically. ROCKII(-/-) dorsal root ganglion neurons are less sensitive to inhibition by Nogo protein or by chondroitin sulfate proteoglycan in vitro. We examined adult ROCKII(-/-) mice in two injury paradigms, cervical multilevel dorsal rhizotomy and midthoracic dorsal spinal cord hemisection. After dorsal root crush injury, the ROCKII(-/-) mice recovered use of the affected forepaw more quickly than did controls. Moreover, multiple classes of sensory axons regenerated across the dorsal root entry zone into the spinal cord of mice lacking ROCKII. After the spinal cord injury, ROCKII(-/-) mice showed enhanced local growth of raphespinal axons in the caudal spinal cord and corticospinal axons into the lesion site. Improved functional recovery was not observed by Basso Mouse Scale score following dorsal hemisection, likely due to developmental defects in the nervous system. Together, these findings demonstrate that the ROCKII gene product limits axonal growth after CNS trauma.
Duffy
Philip
P
Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Schmandke
Andre
A
Schmandke
Antonio
A
Sigworth
Jonathan
J
Narumiya
Shuh
S
Cafferty
William B J
WB
Strittmatter
Stephen M
SM
D000577:Amides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology; D056547:CA1 Region, Hippocampal / Q000166:cytology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020423:Median Neuropathy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000494:pharmacology; D009416:Nerve Regeneration / Q000502:physiology; D009474:Neurons / Q000145:classification / Q000187:drug effects / Q000473:pathology; D000070798:Nogo Proteins; D011725:Pyridines / Q000494:pharmacology; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D019051:Rhizotomy / Q000379:methods; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors; D053675:Versicans / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000172:deficiency / Q000502:physiology*
D000577:Amides; D004791:Enzyme Inhibitors; D009185:Myelin Proteins; D000070798:Nogo Proteins; D011725:Pyridines; C000603199:RTN4 protein, human; D018015:Receptors, Calcitonin Gene-Related Peptide; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat; C508323:Vcan protein, mouse; D053675:Versicans; C108830:Y 27632; D002772:Cholera Toxin; D054460:rho-Associated Kinases