Nature Medicine
6, 1109 - 1114 (2000)
doi:10.1038/80442
Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase
gene or by sphingosine -1-phosphate therapyYutaka Morita1, 6, Gloria I. Perez1, 6, Francois Paris2, Silvia R. Miranda3, Desiree Ehleiter2, Adrianna Haimovitz-Friedman4, Zvi Fuks4, Zhihua Xie5, John C. Reed5, Edward H. Schuchman3, Richard N. Kolesnick2
& Jonathan L. Tilly11
Vincent Center for Reproductive Biology, Department
of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical
School, Boston, Massachusetts 02114,
USA
2
Laboratory of Signal Transduction, Memorial Sloan-Kettering
Cancer Center, New York, New York 10021,
USA
3
Department of Human Genetics, Mount Sinai School of
Medicine, New York, New York 10029,
USA
4
Department of Radiation Oncology, Memorial Sloan-Kettering
Cancer Center, New York, New York 10021,
USA
5
Program on Apoptosis and Cell Death Research, The Burnham
Institute, La Jolla, California 92037,
USA
6
Y.M. and G.I.P. contributed equally to this work
Correspondence should be addressed to Jonathan L. Tilly jtilly@partners.orgThe 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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