Male germ cells require polyenoic sphingolipids with complex glycosylation for completion of meiosis: a link to ceramide synthase-3.
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.
Rabionet
Mariona
M
Department of Cellular and Molecular Pathology, German Cancer Research Center, INF 280, 69120 Heidelberg, Germany.
van der Spoel
Aarnoud C
AC
Chuang
Chia-Chen
CC
von Tümpling-Radosta
Benita
B
Litjens
Manja
M
Bouwmeester
Diane
D
Hellbusch
Christina C
CC
Körner
Christian
C
Wiegandt
Herbert
H
Gorgas
Karin
K
Platt
Frances M
FM
Gröne
Hermann-Josef
HJ
Sandhoff
Roger
R
D000375:Aging / Q000502:physiology; D000818:Animals; D002474:Cell-Free System; D015971:Gene Expression Regulation, Enzymologic; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007248:Infertility, Male; D008297:Male; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D013091:Spermatogenesis; D013107:Sphingolipids / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D015854:Up-Regulation
D012333:RNA, Messenger; D013107:Sphingolipids; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D016695:Glycosyltransferases