The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar.
Axons fail to regenerate in the central nervous system after injury. Chondroitin sulfate proteoglycans (CSPG) expressed in the scar significantly contribute to the nonpermissive properties of the central nervous system environment. To examine the inhibitory activity of a CSPG mixture on retina ganglion cell (RGC) axon growth, we employed both a stripe assay and a nerve fiber outgrowth assay. We show that the inhibition exerted by CSPGs in vitro can be blocked by application of either C3 transferase, a specific inhibitor of the Rho GTPase, or Y27632, a specific inhibitor of the Rho kinase. These results demonstrate that CSPG-associated inhibition of neurite outgrowth is mediated by the Rho/ROCK signaling pathway. Consistent with these results, we found that retina ganglion cell axon growth on glial scar tissue was enhanced in the presence of C3 transferase and Y27632, respectively. In addition, we show that the recently identified inhibitory CSPG Te38 is upregulated in the lesioned spinal cord.
Monnier
Philippe P
PP
Migragen AG, Spemannstrasse 34, D-72076 Tübingen, Germany.
Sierra
Ana
A
Schwab
Jan M
JM
Henke-Fahle
Sigrid
S
Mueller
Bernhard K
BK
D036002:ADP Ribose Transferases / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000201:enzymology; D001905:Botulinum Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D002642:Chick Embryo; D002645:Chickens; D011508:Chondroitin Sulfate Proteoglycans / Q000494:pharmacology*; D002921:Cicatrix / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015696:Gene Products, tat / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D016501:Neurites / Q000201:enzymology*; D009457:Neuroglia / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000201:enzymology; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000503:physiopathology; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases
D000577:Amides; D011508:Chondroitin Sulfate Proteoglycans; D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D011993:Recombinant Fusion Proteins; C108830:Y 27632; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; D020741:rho GTP-Binding Proteins