Brown, Joshua M. and Xia, Jiang and Zhuang, BinQuan and Cho, Kin-Sang and Rogers, Claude J. and Gama, Cristal I. and Rawat, Manish and Tully, Sarah E. and Uetani, Noriko and Mason, Daniel E. and Tremblay, Michel L. and Peters, Eric C. and Habuchi, Osami and Chen, Dong F. and Hsieh-Wilson, Linda C. (2012) A sulfated carbohydrate epitope inhibits axon regeneration after injury. Proceedings of the National Academy of Sciences of the United States of America, 109 (13). pp. 4768-4773. ISSN 0027-8424 http://resolver.caltech.edu/CaltechAUTHORS:20120423-132028059
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Chondroitin sulfate proteoglycans (CSPGs) represent a major barrier to regenerating axons in the central nervous system (CNS), but the structural diversity of their polysaccharides has hampered efforts to dissect the structure-activity relationships underlying their physiological activity. By taking advantage of our ability to chemically synthesize specific oligosaccharides, we demonstrate that a sugar epitope on CSPGs, chondroitin sulfate-E (CS-E), potently inhibits axon growth. Removal of the CS-E motif significantly attenuates the inhibitory activity of CSPGs on axon growth. Furthermore, CS-E functions as a protein recognition element to engage receptors including the transmembrane protein tyrosine phosphatase PTPσ, thereby triggering downstream pathways that inhibit axon growth. Finally, masking the CS-E motif using a CS-E-specific antibody reversed the inhibitory activity of CSPGs and stimulated axon regeneration in vivo. These results demonstrate that a specific sugar epitope within chondroitin sulfate polysaccharides can direct important physiological processes and provide new therapeutic strategies to regenerate axons after CNS injury.
|Additional Information:||© 2012 by the National Academy of Sciences. Edited by Peter G. Schultz, The Scripps Research Institute, La Jolla, CA, and approved January 23, 2012 (received for review December 27, 2011). Published online before print March 12, 2012. We thank J. Vielmetter, Director of the Caltech Protein Expression Center, for assistance with the surface plasmon resonance analysis, I. Antoshechkin and the Caltech Millard and Muriel Jacobs Genetics and Genomics Laboratory for printing of the polysaccharide microarrays, and P. Clark for helpful comments on the manuscript. This research was supported by National Institutes of Health grants R01 GM093627-03 (L.H.W.) and 5T32 GM07616-30S1 (J.M.B.), the Roman Reed Spinal Cord Injury Research Fund of California (L.H.W.), and a Christopher & Dana Reeve Foundation Individual Research Grant (B.Z.). Author contributions: J.M.B., J.X., B.Z., and L.C.H.-W. designed research; J.M.B., J.X., B.Z., K.-S.C., C.J.R., C.I.G., S.E.T., and D.E.M. performed research; M.R., S.E.T., N.U., M.L.T., and O.H. contributed new reagents/analytic tools; J.M.B., J.X., B.Z., K.-S.C., C.J.R., C.I.G., D.E.M., E.C.P., D.F.C., and L.C.H.-W. analyzed data; and J.M.B., B.Z., D.F.C., and L.C.H.-W. wrote the paper.|
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|Deposited By:||Tony Diaz|
|Deposited On:||23 Apr 2012 21:38|
|Last Modified:||26 Dec 2012 15:06|
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