Abstract
Sphingolipids and the derived gangliosides have critical functions in spermatogenesis, thus mutations in genes involved in sphingolipid biogenesis are often associated with male infertility. We have generated a transgenic mouse line carrying an insertion in the sphingomyelin synthase gene Sms1, the enzyme which generates sphingomyelin species in the Golgi apparatus. We describe the spermatogenesis defect of Sms1-/- mice, which is characterized by sloughing of spermatocytes and spermatids, causing progressive infertility of male homozygotes. Lipid profiling revealed a reduction in several long chain unsaturated phosphatidylcholins, lysophosphatidylcholins and sphingolipids in the testes of mutants. Multi-Spectral Optoacoustic Tomography indicated blood-testis barrier dysfunction. A supplementary diet of the essential omega-3 docosahexaenoic acid and eicosapentaenoic acid diminished germ cell sloughing from the seminiferous epithelium and restored spermatogenesis and fertility in 50% of previously infertile mutants. Our findings indicate that SMS1 has a wider than anticipated role in testis polyunsaturated fatty acid homeostasis and for male fertility.
MeSH terms
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Aging / physiology
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Alternative Splicing
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Animals
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Epididymis / drug effects
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Epididymis / metabolism
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Fatty Acids, Omega-3 / biosynthesis
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Fatty Acids, Omega-3 / pharmacology
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Fertility* / drug effects
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Infertility, Male / enzymology
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Lipid Metabolism / drug effects
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Male
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Mice
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Mutagenesis, Insertional
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Promoter Regions, Genetic / genetics
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Spermatogenesis / drug effects
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Testis / drug effects
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Testis / metabolism
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Transferases (Other Substituted Phosphate Groups) / genetics
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Transferases (Other Substituted Phosphate Groups) / metabolism*
Substances
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Fatty Acids, Omega-3
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Sgms1 protein, mouse
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Transferases (Other Substituted Phosphate Groups)
Grants and funding
This work was funded by the KNDD2 grants FKZ 01 GI 1005D to T.F. This work was also funded by the program for medical genome research with financial support from the NGFNplus grant "Funktionelle Tiermodelle für die Kandidatengene der Alzheimerschen Erkrankung" (01GS08133), the Federal Ministry for Education and Research (BMBF) grant "Charakterisierung genetischer Mausmodelle für die Parkinsonsche Erkrankung" under the support code 01GS08174, the grant "Verhalten" 01GS0850, furthermore by the Helmholtz Alliance “Mental Health in an Ageing Society” (HELMA) (HA215). This study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). The GMC was supported by NGFNplus (01GS0850) and Infrafrontier (01KX1012) grants from the BMBF and the EU (EUMODIC LSHG-2006-037188). This work was supported by grants to JB from the National Genome Research Network (NGFN 01GR). This work was supported by grants the NGFNplus grant PNA-01GS08129-5 and EFRE/Kowi funding on basis of grant C/4-EFRE-11/2008/KA to TH and by the DFG priority program sphingolipids to TH and MOWG.