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Semaphorin 3A Binds to the Perineuronal Nets via Chondroitin Sulfate Type E Motifs in Rodent Brains

Dick, Gunnar and Tan, Chin Lik and Alves, Joao Nuno and Ehlert, Erich M. and Miller, Gregory M. and Hsieh-Wilson, Linda C. and Sugahara, Kazuyuki and Oosterhof, Arie and van Kuppevelt, Toin H. and Verhaagen, Joost and Fawcett, James W. and Kwok, Jessica C. F. (2013) Semaphorin 3A Binds to the Perineuronal Nets via Chondroitin Sulfate Type E Motifs in Rodent Brains. Journal of Biological Chemistry, 288 (38). pp. 27384-27395. ISSN 0021-9258. PMCID PMC3779733.

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Chondroitin sulfate (CS) and the CS-rich extracellular matrix structures called perineuronal nets (PNNs) restrict plasticity and regeneration in the CNS. Plasticity is enhanced by chondroitinase ABC treatment that removes CS from its core protein in the chondroitin sulfate proteoglycans or by preventing the formation of PNNs, suggesting that chondroitin sulfate proteoglycans in the PNNs control plasticity. Recently, we have shown that semaphorin3A (Sema3A), a repulsive axon guidance molecule, localizes to the PNNs and is removed by chondroitinase ABC treatment (Vo, T., Carulli, D., Ehlert, E. M., Kwok, J. C., Dick, G., Mecollari, V., Moloney, E. B., Neufeld, G., de Winter, F., Fawcett, J. W., and Verhaagen, J. (2013) Mol. Cell. Neurosci. 56C, 186–200). Sema3A is therefore a candidate for a PNN effector in controlling plasticity. Here, we characterize the interaction of Sema3A with CS of the PNNs. Recombinant Sema3A interacts with CS type E (CS-E), and this interaction is involved in the binding of Sema3A to rat brain-derived PNN glycosaminoglycans, as demonstrated by the use of CS-E blocking antibody GD3G7. In addition, we investigate the release of endogenous Sema3A from rat brain by biochemical and enzymatic extractions. Our results confirm the interaction of Sema3A with CS-E containing glycosaminoglycans in the dense extracellular matrix of rat brain. We also demonstrate that the combination of Sema3A and PNN GAGs is a potent inhibitor of axon growth, and this inhibition is reduced by the CS-E blocking antibody. In conclusion, Sema3A binding to CS-E in the PNNs may be a mechanism whereby PNNs restrict growth and plasticity and may represent a possible point of intervention to facilitate neuronal plasticity.

Item Type:Article
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Hsieh-Wilson, Linda C.0000-0001-5661-1714
Additional Information:© 2013 The American Society for Biochemistry and Molecular Biology, Inc. Received for publication,May 31, 2013, and in revised form, July 20, 2013; published, JBC Papers in Press, August 12, 2013. We thank Dr. Gerdy B. ten Dam for advice on the purification and use of the antibodies GD3G7 and MPB49V. We also thank Dr. Antoshechkin and the Caltech Millard and Muriel Jacobs Genetics and Genomics Laboratory for assistance with printing of the polysaccharide microarrays. This work was supported, in whole or in part, by National Institutes of Health Grant R01 GM093627 (to L. H. W.). This work was also supported by The Christopher and Dana Reeve Foundation (to J. W. F. and L. H. W.), Wings for Life (to J. C. F. K.), European Union FP7 Programme AxRegen, and Grants-in-aid for Scientific Research on Innovative Areas 24110501 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) (to K. S.).
Funding AgencyGrant Number
NIHR01 GM093627
Christopher and Dana Reeve FoundationUNSPECIFIED
European Union FP7 ProgrammeAxRegen
Ministry of Education, Culture, Sports, Science and Technology (MEXT)24110501
Subject Keywords:Chondroitin Sulfate; Glycosaminoglycan; Proteoglycan; Regeneration; Semaphorin; Semaphorin3A; Neuronal Plasticity; Perineuronal nets
Issue or Number:38
PubMed Central ID:PMC3779733
Record Number:CaltechAUTHORS:20140227-132857283
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Official Citation:Dick, G., Tan, C. L., Alves, J. N., Ehlert, E. M. E., Miller, G. M., Hsieh-Wilson, L. C., . . . Kwok, J. C. F. (2013). Semaphorin 3A Binds to the Perineuronal Nets via Chondroitin Sulfate Type E Motifs in Rodent Brains. Journal of Biological Chemistry, 288(38), 27384-27395.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:44039
Deposited By: Jason Perez
Deposited On:28 Feb 2014 15:34
Last Modified:03 Oct 2019 06:13

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