Morita Y, Perez G I, Paris F, Miranda S R, Ehleiter D, Haimovitz-Friedman A, Fuks Z, Xie Z, Reed J C, Schuchman E H, Kolesnick R N, Tilly J L
Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
Nat Med. 2000 Oct;6(10):1109-14. doi: 10.1038/80442.
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.
雌性动物卵巢衰竭（绝经）发生的时间，由出生时所提供的卵母细胞储备数量，以及在出生后整个生命过程中该储备的消耗速率所决定。我们在此表明，雌性小鼠中酸性鞘磷脂酶基因的破坏抑制了胎儿期卵母细胞正常的凋亡性清除，导致新生小鼠卵巢增生。在体外，缺乏酸性鞘磷脂酶基因的卵母细胞或用1-磷酸鞘氨醇处理的野生型卵母细胞可抵抗发育性凋亡以及抗癌治疗诱导的凋亡，证实了死亡缺陷的细胞自主性。此外，成年野生型雌性小鼠中辐射诱导的卵母细胞丢失，这一导致女性癌症患者卵巢早衰和不孕的事件，通过体内注射1-磷酸鞘氨醇治疗可完全预防。因此，鞘磷脂途径调节卵母细胞的发育性死亡，且1-磷酸鞘氨醇为体内保留卵巢功能提供了一种新方法。
