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J. Biol. Chem., Vol. 283, Issue 24, 16885-16894, June 13, 2008

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Altered Heparan Sulfate Structure in Mice with Deleted NDST3 Gene Function^*

Srinivas R. Pallerla, Roger Lawrence, Lars Lewejohann^¶, Yi Pan^||, Tobias Fischer^**, Uwe Schlomann, Xin Zhang^||, Jeffrey D. Esko, and Kay Grobe¹

From the Department of General Zoology and Genetics, the Institute for Physiological Chemistry and Pathobiochemistry, and the ^¶Department of Behavioural Biology, Westfälische Wilhelms-Universität Münster, Schlossplatz 5, Münster D-48149, Germany, the Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093, the ^||Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, and the ^**Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Göttingen 37075

We report the generation and analysis of mutant mice bearing a targeted disruption of the heparan sulfate (HS)-modifying enzyme GlcNAc N-deacetylase/N-sulfotransferase 3 (NDST3). NDST3^-/- mice develop normally, are fertile, and show only subtle hematological and behavioral abnormalities in agreement with only moderate HS undersulfation. Compound mutant mice made deficient in NDST2;NDST3 activities also develop normally, showing that both isoforms are not essential for development. In contrast, NDST1^-/-;NDST3^-/- compound mutant embryos display developmental defects caused by severe HS undersulfation, demonstrating NDST3 contribution to HS synthesis in the absence of NDST1. Moreover, analysis of HS composition in dissected NDST3 mutant adult brain revealed regional changes in HS sulfation, indicating restricted NDST3 activity on nascent HS in defined wild-type tissues. Taken together, we show that NDST3 function is not essential for development or adult homeostasis despite contributing to HS synthesis in a region-specific manner and that the loss of NDST3 function is compensated for by the other NDST isoforms to a varying degree.

Received for publication, November 29, 2007 , and in revised form, February 28, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM33063 and HL57345 (to J. D. E.). This work was also supported by DFG (German Research Council) Grants GR1748 and SFB 492-B15 (to K. G.). The authors state that they have no competing interests. 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 Figs. S1 and S2.

¹ To whom correspondence should be addressed: Tel.: 49-251-8323-886; Fax: 49-251-832-4723; E-mail: kgrobe{at}uni-muenster.de.

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