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Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine -1-phosphate therapy

Abstract

The time at which ovarian failure (menopause) occurs in females is determined by the size of the oocyte reserve provided at birth, as well as by the rate at which this endowment is depleted throughout post-natal life. Here we show that disruption of the gene for acid sphingomyelinase in female mice suppressed the normal apoptotic deletion of fetal oocytes, leading to neonatal ovarian hyperplasia. Ex vivo, oocytes lacking the gene for acid sphingomyelinase or wild-type oocytes treated with sphingosine-1-phosphate resisted developmental apoptosis and apoptosis induced by anti-cancer therapy, confirming cell autonomy of the death defect. Moreover, radiation-induced oocyte loss in adult wild-type female mice, the event that drives premature ovarian failure and infertility in female cancer patients, was completely prevented by in vivo therapy with sphingosine-1-phosphate. Thus, the sphingomyelin pathway regulates developmental death of oocytes, and sphingosine-1-phosphate provides a new approach to preserve ovarian function in vivo.

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Figure 1: Post-natal oocyte hyperplasia results from disruption of SMPD1.
Figure 2: SMPD1 deficiency or S1P treatment attenuates apoptosis in female germ cells during fetal gametogenesis.
Figure 3: Cell-autonomous nature of the oocyte death defect caused by disruption of SMPD1 or treatment with S1P.
Figure 4: The protective actions of S1P in oocytes are not mimicked by LPA and are insensitive to pertussis toxin.
Figure 5: In vivo S1P administration protects ovaries from radiation-induced damage.
Figure 6: Protection of ovaries by S1P during radiotherapy in vivo yields oocytes with normal embryonic developmental potential.

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Acknowledgements

The authors thank I. Schiff for discussions after his critical review of the manuscript before its submission, and S. Riley for technical assistance with the image analysis and data presentation. This study was supported by National Institutes of Health grants R01-AG12279 (J.L.T.), R01-HD34226 (J.L.T.), R01-ES08430 (J.L.T.) and R01- CA423852 (R.N.K.), and by Vincent Memorial Research Funds (J.L.T.). This work was done while Y.M. was on leave from the Department of OB/GYN of the University of Tokyo Faculty of Medicine and supported by the Japanese Society for the Promotion of Science, and while G.I.P. was supported in part by a grant from the Harvard Center of Excellence in Women's Health.

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Correspondence to Jonathan L. Tilly.

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Morita, Y., Perez, G., Paris, F. et al. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine -1-phosphate therapy. Nat Med 6, 1109–1114 (2000). https://doi.org/10.1038/80442

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