Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy.
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.
Morita
Y
Y
Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
Perez
G I
GI
Paris
F
F
Miranda
S R
SR
Ehleiter
D
D
Haimovitz-Friedman
A
A
Fuks
Z
Z
Xie
Z
Z
Reed
J C
JC
Schuchman
E H
EH
Kolesnick
R N
RN
Tilly
J L
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009865:Oocytes / Q000166:cytology* / Q000187:drug effects* / Q000528:radiation effects; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics* / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D008246:Lysophospholipids; D013109:Sphingomyelins; C060506:sphingosine 1-phosphate; D004317:Doxorubicin; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine