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 determin ed by the size of the oocyte reserve provided at birth, as well as by the r ate 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 neona tal ovarian hyperplasia. Ex vivo, oocytes lacking the gene for acid sphingo myelinase or wild-type oocytes treated with sphingosine-1-phosphate resiste d developmental apoptosis and apoptosis induced by anti-cancer therapy, con firming cell autonomy of the death defect. Moreover, radiation-induced oocy te loss in adult wild-type female mice, the event that drives premature ova rian failure and infertility in female cancer patients, was completely prev ented by in vivo therapy with sphingosine-1-phosphate. Thus, the sphingomye lin pathway regulates developmental death of oocytes, and sphingosine-1-pho sphate provides a new approach to preserve ovarian function in vivo.