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J. Biol. Chem., Vol. 282, Issue 27, 19589-19597, July 6, 2007

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Essential Role of Heparan Sulfate 2-O-Sulfotransferase in Chick Limb Bud Patterning and Development^*

Takashi Kobayashi, Hiroko Habuchi, Koji Tamura, Hiroyuki Ide, and Koji Kimata¹

From the Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan and Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama Aobaku, Sendai 980-8578, Japan

The interactions of heparan sulfate (HS) with heparin-binding growth factors, such as fibroblast growth factors (FGFs), depend greatly on the chain structures. O-Sulfations at various positions on the chain are major factors determining HS structure; therefore, O-sulfation patterns may play a crucial role in controlling the developmental and morphogenetic processes of various tissues and organs by spatiotemporally regulating the activities of heparin-binding growth factors. In a previous study, we found that HS-2-O-sulfotransferase is strongly expressed throughout the mesoderm of chick limb buds during the early stages of development. Here we show that inhibition of HS-2-O-sulfotransferase in the prospective limb region by small inhibitory RNA resulted in the truncation of limb buds and reduced Fgf-8 expression in the apical ectodermal ridge. The treatment also reduced Fgf-10 expression in the mesenchyme. Moreover 2-O-sulfated HS, normally abundant in the basement membranes and mesoderm under ectoderm in limb buds, was significantly reduced in the treated buds. Phosphorylation levels of ERK and Akt were up-regulated in such truncated buds. Thus, we have shown for the first time that 2-O-sulfation of HS is essential for the FGF signaling required for limb bud development and outgrowth.

Received for publication, November 20, 2006 , and in revised form, May 4, 2007.

^* This work was supported by Grant-in-aid for Scientific Research on Priority Areas 14082206 from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by a special research fund from the 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed. Tel.: 81-561-62-3311 (ext. 2088); Fax: 81-561-63-3532; E-mail: kimata{at}amugw.aichi-med-u.ac.jp.

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