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J. Biol. Chem., Vol. 282, Issue 21, 15578-15588, May 25, 2007

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Mice Deficient in Heparan Sulfate 6-O-Sulfotransferase-1 Exhibit Defective Heparan Sulfate Biosynthesis, Abnormal Placentation, and Late Embryonic Lethality^*

Hiroko Habuchi, Naoko Nagai, Noriko Sugaya, Fukiko Atsumi, Richard L. Stevens^¶, and Koji Kimata¹

From the Institute for Molecular Science of Medicine and Laboratory Animal Research Center, Aichi Medical University, Nagakute, Aichi 480-1195, Japan and the ^¶Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115

Heparan sulfate (HS) plays critical roles in a variety of developmental, physiological, and pathogenic processes due to its ability to interact in a structure-dependent manner with numerous growth factors that participate in cellular signaling. The divergent structures of HS glycosaminoglycans are the result of the coordinate actions of several N- and O-sulfotransferases, C5-epimerase, and 6-O-endosulfatases. We have shown that 6-O-sulfation of the glucosamine residues in HS are catalyzed by the sulfotransferases HS6ST-1, -2, and -3. To determine the biological and physiological importance of HS6ST-1, we now describe the creation of transgenic mice that lack this sulfotransferase. Most of our HS6ST-1-null mice died between embryonic day 15.5 and the perinatal stage, and those mice that survived were considerably smaller than their wild-type littermates. Some of these HS6ST-1-null mice exhibited development abnormalities, and histochemical and molecular analyses of these mice revealed an 50% reduction in the number of fetal microvessels in the labyrinthine zone of the placenta relative to that in the wild-type mice. Because we observed a modest reduction in VEGF-A mRNA and protein in the tissues of HS6ST-1-null mice, an HS-dependent defect in cytokine signaling probably contributes to increased embryonic lethality and decreased growth. Biochemical studies of the HS chains isolated from various organs of our HS6ST-1-null mice revealed a marked reduction of GlcNAc(6SO₄) and HexA-GlcNSO₃(6SO₄) levels and a reduced ability to bind Wnt2. Thus, despite the presence of three closely related 6-O-sulfotransferase genes in the mouse genome, HS6ST-1 is the primary one used in HS biosynthesis in most tissues.

Received for publication, August 4, 2006 , and in revised form, March 27, 2007.

^* This work was supported by a Japan Society for the Promotion of Science grant-in-aid for the promotion of science, by Grants-in-aid for Scientific Research on Priority Areas 14082206 and 17570099 from the Ministry of Education, Culture, Sport, Science, and Technology of Japan, by National Institutes of Health Grant HL036110 (to R. L. S.), and by a special research fund from Seikagaku Corp. 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.

¹ To whom correspondence should be addressed: Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan. Tel.: 81-52-264-4811; Fax: 81-561-63-3532; E-mail: kimata{at}aichi-med-u.ac.jp.

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