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J. Biol. Chem., Vol. 282, Issue 27, 19442-19452, July 6, 2007

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Functions of Chondroitin Sulfate/Dermatan Sulfate Chains in Brain Development

CRITICAL ROLES OF E AND iE DISACCHARIDE UNITS RECOGNIZED BY A SINGLE CHAIN ANTIBODY GD3G7^*

Anurag Purushothaman¹, Junko Fukuda, Shuji Mizumoto, Gerdy B. ten Dam^¶, Toin H. van Kuppevelt^¶, Hiroshi Kitagawa, Tadahisa Mikami, and Kazuyuki Sugahara²

From the Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan, the Laboratory of Proteoglycan Signaling and Therapeutics, Graduate School of Life Science, Hokkaido University, Frontier Research Center for Post-Genomic Science and Technology, Nishi 11-choume, Kita 21-jo, Kita-ku, Sapporo, Hokkaido 001-0021, Japan, and the^¶Department of Biochemistry, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands

Chondroitin sulfate (CS) and dermatan sulfate (DS) have been implicated in the processes of neural development in the brain. In this study, we characterized developmentally regulated brain CS/DS chains using a single chain antibody, GD3G7, produced by the phage display technique. Evaluation of the specificity of GD3G7 toward various glycosaminoglycan preparations showed that this antibody specifically reacted with squid CS-E (rich in the GlcUA1–3GalNAc(4,6-O-sulfate) disaccharide unit E), hagfish CS-H (rich in the IdoUA1–3GalNAc(4,6-O-sulfate) unit iE), and shark skin DS (rich in both E and iE units). In situ hybridization for the expression of N-acetylgalac-tosamine-4-sulfate 6-O-sulfotransferase in the postnatal mouse brain, which is involved in the biosynthesis of CS/DS-E, showed a widespread expression of the transcript in the developing brain except at postnatal day 7, where strong expression was observed in the external granule cell layer in the cerebellum. The expression switched from the external to internal granule cell layer with development. Immunohistochemical localization of GD3G7 in the mouse brain showed that the epitope was relatively abundant in the cerebellum, hippocampus, and olfactory bulb. GD3G7 suppressed the growth of neurites in embryonic hippocampal neurons mediated by CS-E, suggesting that the epitope is embedded in the neurite outgrowth-promoting motif of CS-E. In addition, a CS-E decasaccharide fraction was found to be the critical minimal structure needed for recognition by GD3G7. Four discrete decasaccharide epitopic sequences were identified. The antibody GD3G7 has broad applications in investigations of CS/DS chains during the central nervous system's development and under various pathological conditions.

Received for publication, January 23, 2007 , and in revised form, April 27, 2007.

^* The work performed in Kobe was supported in part by Scientific Research Promotion Fund from the Japan Private School Promotion Foundation Grants-in-aid 17659020, 18390030, and 14082207 and Encouragement of Young Scientists Grant 18790073 (to T. M.) from MEXT, the Human Frontier Science Program, The New Energy and Industrial Technology Development Organization, and the Core Research for Evolutional Science and Technology program of the Japan Science and Technology Agency. The work in Nijmegen was supported by Dutch Cancer Society Grant 2002-2762 (to G. t. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org contains supplemental Fig. S1.

¹ Supported by a postdoctoral fellowship of HAITEKU (2004–2005) from the Japan Private School Promotion Foundation.

² To whom correspondence should be addressed. Tel.: 81-11-706-9054; Fax: 81-11-706-9056; E-mail: k-sugar{at}sci.hokudai.ac.jp.

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