Suppression of Rho-kinase activity promotes axonal growth on inhibitory CNS substrates.
Several molecules inhibit axonal growth cones and may account for the failure of central nervous system regeneration, including myelin proteins and various chondroitan sulfate proteoglycans expressed at the site of injury. Axonal growth inhibition by myelin and chondroitan sulfate proteoglycans may in part be controlled by Rho-GTPase, which mediates growth cone collapse. Here, we tested in vitro whether pharmacological inhibition of a major downstream effector of Rho, Rho-kinase, promotes axonal outgrowth from dorsal root ganglia grown on aggrecan. Aggrecan substrates stimulated Rho activity and were inhibitory to axonal growth. Y-27632 treatment promoted the growth of axons by 5- to 10-fold and induced "steamlined" growth cones with longer filopodia and smaller lamellipodia. Interestingly, more actin bundles reminiscent of stress fibers in the central domain of the growth cone were observed when grown on aggrecan compared to laminin. In addition, Y-27632 significantly promoted axonal growth on both myelin and adult rat spinal cord cryosections. Our data suggest that suppression of Rho-kinase activity may enhance axonal regeneration in the central nervous system.
Borisoff
Jaimie F
JF
CORD (Collaboration on Repair Discoveries), University of British Columbia, 6270 University Blvd., V6T 1Z4, Vancouver, British Columbia, Canada.
Chan
Carmen C M
CC
Hiebert
Gordon W
GW
Oschipok
Loren
L
Robertson
George S
GS
Zamboni
R
R
Steeves
John D
JD
Tetzlaff
Wolfram
W
D053674:Aggrecans; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000201:enzymology*; D002642:Chick Embryo; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins; D005727:Ganglia, Spinal / Q000166:cytology; D020439:Growth Cones / Q000187:drug effects / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D009185:Myelin Proteins / Q000494:pharmacology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000201:enzymology* / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011509:Proteoglycans / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology; D054460:rho-Associated Kinases
C508321:Acan protein, rat; D053674:Aggrecans; D000577:Amides; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D009185:Myelin Proteins; D011509:Proteoglycans; D011725:Pyridines; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases