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J. Biol. Chem., Vol. 280, Issue 6, 4858-4863, February 11, 2005

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Egghead and Brainiac Are Essential for Glycosphingolipid Biosynthesis in Vivo^*

Hans H. Wandall, Sandrine Pizette¶, Johannes W. Pedersen, Heather Eichert||, Steven B. Levery||, Ulla Mandel, Stephen M. Cohen¶**, and Henrik Clausen

From the Faculty of Health Sciences, University of Copenhagen, Nørre Allé 20, 2200 Copenhagen N, Denmark, the ^¶European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany, and the ^||Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824

The Drosophila genes, brainiac and egghead, encode glycosyltransferases predicted to act sequentially in early steps of glycosphingolipid biosynthesis, and both genes are required for development in Drosophila. egghead encodes a 4-mannosyltransferase, and brainiac encodes a 3-N-acetylglucosaminyltransferase predicted by in vitro analysis to control synthesis of the glycosphingolipid core structure, GlcNAc1–3Man1–4Glc1-Cer, found widely in invertebrates but not vertebrates. In this report we present direct in vivo evidence for this hypothesis. egghead and brainiac mutants lack elongated glycosphingolipids and exhibit accumulation of the truncated precursor glycosphingolipids. Furthermore, we demonstrate that despite fundamental differences in the core structure of mammalian and Drosophila glycosphingolipids, the Drosophila egghead mutant can be rescued by introduction of the mammalian lactosylceramide glycosphingolipid biosynthetic pathway (Gal1–4Glc1-Cer) using a human 4-galactosyltransferase (4Gal-T6) transgene. Conversely, introduction of egghead in vertebrate cells (Chinese hamster ovary) resulted in near complete blockage of biosynthesis of glycosphingolipids and accumulation of Man1–4Glc1-Cer. The study demonstrates that glycosphingolipids are essential for development of complex organisms and suggests that the function of the Drosophila glycosphingolipids in development does not depend on the core structure.

Received for publication, December 9, 2004 , and in revised form, December 13, 2004.

^* This work was supported by the Human Science Frontier Program (RGP0063/2002-C), the Velux Foundation, the Danish Medical Research Council, National Institutes of Health Grants P41 RR05351 and P20 RR16459, and European Community Marie Curie Fellowship IHP HPMF-CT-2000–01083. 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.

These two authors contributed equally.

^** To whom correspondence may be addressed: Developmental Biology Unit, EMBL, Meyerhofstr. 1, 69117 Heidelberg, Germany. Tel.: 49-6221-387-414; Fax: 49-6221-387-166; E-mail: Stephen.Cohen{at}embl-heidelberg.de. To whom correspondence may be addressed: Faculty of Health Sciences, University of Copenhagen, Nørre Alle 20, DK-2200 N, Denmark. Tel.: 45-35326630; Fax: 45-35326835; E-mail: hc{at}odont.ku.dk.

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