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J. Biol. Chem., Vol. 283, Issue 19, 13357-13369, May 9, 2008

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Male Germ Cells Require Polyenoic Sphingolipids with Complex Glycosylation for Completion of Meiosis

A LINK TO CERAMIDE SYNTHASE-3^*

Mariona Rabionet, Aarnoud C. van der Spoel¹, Chia-Chen Chuang, Benita von Tümpling-Radosta, Manja Litjens², Diane Bouwmeester³, Christina C. Hellbusch^¶, Christian Körner^¶, Herbert Wiegandt, Karin Gorgas^||, Frances M. Platt, Hermann-Josef Gröne, and Roger Sandhoff⁴

From the Department of Cellular and Molecular Pathology, German Cancer Research Center, INF 280, 69120 Heidelberg, Germany, the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom, the ^¶Department of Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, INF 153, 69120 Heidelberg, Germany, and the ^||Department of Anatomy and Cell Biology II, University of Heidelberg, INF 307, 69120 Heidelberg, Germany

Previously, it was found that a novel class of neutral fucosylated glycosphingolipids (GSLs) is required for male fertility. These lipids contain very long-chain (C26-C32) polyunsaturated (4-6 double bonds) fatty acid residues (VLC-PUFAs). To assess the role of these complex GSLs in spermatogenesis, we have now investigated with which of the testicular cell types these lipids are associated. During postnatal development, complex glycosylated and simple VLC-PUFA sphingolipids were first detectable at day 15, when the most advanced germ cells are pachytene spermatocytes. Their synthesis is most likely driven by ceramide synthase-3. This enzyme is encoded by the Cers3/Lass3 gene (longevity assurance genes), and out of six members of this gene family, only Cers3 mRNA expression was limited to germ cells, where it was up-regulated more than 700-fold during postnatal testicular maturation. Increasing levels of neutral complex VLC-PUFA GSLs also correlated with the progression of spermatogenesis in a series of male sterile mutants with arrests at different stages of spermatogenesis. Remarkably, fucosylation of the complex VLC-PUFA GSLs was not essential for spermatogenesis, as fucosylation-deficient mice produced nonfucosylated versions of the complex testicular VLC-PUFA GSLs, had complete spermatogenesis, and were fertile. Nevertheless, sterile Galgt1^-/- mice, with a defective meiotic cytokinesis and a subsequent block in spermiogenesis, lacked complex but contained simple VLC-PUFA GSLs, as well as VLC-PUFA ceramides and sphingomyelins, indicating that the latter lipids are not sufficient for completion of spermatogenesis. Thus, our data imply that both glycans and the particular acyl chains of germinal sphingolipids are relevant for proper completion of meiosis.

Received for publication, February 1, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant 1 U01 HD45861 (to A. C. S. and F. M. P.). This work was also supported by the German Research Foundation Grants SA 1721/1-1 and GO 432/2-1, Schering AG (to C. C. C.), and the Oxford Glycobiology Institute endowment. 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 Experimental Procedures, additional references, Table 1, and Figs. 1, 2, 3, 4, 5, 6, 7 and 8.

² Present address: Dept. of Molecular Cell Biology and Immunology, Free University Medical Center, 1081 BT Amsterdam, The Netherlands.

³ Present address: Dept. of Physiological Chemistry, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.

¹ To whom correspondence may be addressed. E-mail: aarnoud.vanderspoel{at}pharm.ox.ac.uk.

⁴ To whom correspondence may be addressed. E-mail: r.sandhoff{at}dkfz-heidelberg.de.

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