Novel Class of Glycosphingolipids Involved in Male Fertility

Tjeerd P Sijmonsma,Richard Jennemann,Karin Gorgas,Eva Kiss,Roger Sandhoff,Masao Iwamori,Richard L Proia,Herbert Wiegandt,Hermann-Josef Gröne,Catherine Finaz,Rudolf Geyer,Tadashi Yamashita,Claudia Paret

doi:10.1074/jbc.m502775200

Abstract

Mice require testicular glycosphingolipids (GSLs) for proper spermatogenesis. Mutant mice strains deficient in specific genes encoding biosynthetic enzymes of the GSL pathway including Galgt1 (encoding GM2 synthase) and Siat9 (encoding GM3 synthase) have been established lacking various overlapping subsets of GSLs. Although male Galgt1-/- mice are infertile, male Siat9-/- mice are fertile. Interestingly, GSLs thought to be essential for male spermatogenesis are not synthesized in either of these mice strains. Hence, these GSLs cannot account for the different phenotypes. A novel class of GSLs was observed composed of eight fucosylated molecules present in fertile but not in infertile mutant mice. These GSLs contain polyunsaturated very long chain fatty acid residues in their ceramide moieties. GSLs of this class are expressed differentially in testicular germ cells. More importantly, the neutral subset of this new GSL class strictly correlates with male fertility. These data implicate polyunsaturated, fucosylated GSLs as essential for spermatogenesis and male mouse fertility.

Highlights

Mice require testicular glycosphingolipids (GSLs) for proper spermatogenesis
Spermatogenesis proceeds only until the stage of round spermatids, and the string of beads composed of spermatids is thought to lose Sertoli cell contact and round up to multinuclear giant cells [1]
The deficiency of brain type gangliosides in Galgt1Ϫ/Ϫ mice have been linked to male infertility

Summary

Novel Class of Glycosphingolipids Involved in Male Fertility*

Glycosphingolipids (GSLs) are amphipathic molecules present on cell membranes of the endocytotic and exocytotic pathway in mammalian cells where they influence membrane function They appear to play a role in cytological germ cell transformations because male mice lacking complex gangliosides, i.e. sialic acid-containing GSLs, resulting from Galgt deficiency ( known as Galgt encoding Gg3Cer/GM2/GD2synthase (EC 2.4.1.92) are infertile (Fig. 1) [1, 2]. In these mice, spermatogenesis proceeds only until the stage of round spermatids, and the string of beads composed of spermatids is thought to lose Sertoli cell contact and round up to multinuclear giant cells [1]. The ceramide moieties of the novel FGSLs are highly unsaturated and contain polyenoic (four to six double bonds) very long chain fatty acid residues with at least 26 carbon atoms and mostly 2-hydroxylation

EXPERIMENTAL PROCEDURES

Fragments of compounds A or B

RESULTS

Incorporated fatty acid

DISCUSSION