Female mice lacking the gene encoding the prostaglandin (PG) E 2 receptor subtype EP 2 (EP 2 ؊͞؊ ) become pregnant and deliver their pups at term, but with a much reduced litter size. A decrease in ovulation number and a much reduced fertilization rate were observed in EP 2 ؊͞؊ females without difference of the uterus to support implantation of wild-type embryos. Treatment with gonadotropins induced EP 2 mRNA expression in the cumulus cells of ovarian follicles of wild-type mice. The immature cumuli oophori from wildtype mice expanded in vitro in response to both folliclestimulating hormone and PGE 2 , but the response to PGE 2 was absent in those from EP 2 ؊͞؊ mice. Cumulus expansion proceeded normally in preovulatory follicles but became abortive in a number of ovulated complexes in EP 2 ؊͞؊ mice, indicating that EP 2 is involved in cumulus expansion in the oviduct in vivo. No difference in the fertilization rate between wild-type and EP 2 ؊͞؊ mice was found in in vitro studies using cumulusfree oocytes. These results indicate that PGE 2 cooperates with gonadotropin to complete cumulus expansion for successful fertilization.Ovulation and fertilization are key processes in mammalian female reproduction, which is highly regulated by pituitary gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone. These hormones induce a number of preovulatory processes, including follicular development, oocyte maturation, cumulus expansion, and rupture of antral follicles (1). The ovulated eggs move to the oviducts, and timely interaction between an egg and a sperm then leads to successful fertilization (2). Undoubtedly, these processes are initiated by the gonadotropins, but how gonadotropins regulate these processes remains unclear. It is known that some gonadotropin actions are mediated by other mediators. Prostanoids, the cyclooxygenase (COX)-metabolites of arachidonate, likely mediate the ovulatory actions of gonadotropins (3) because aspirin-like drugs that inhibit COX have been reported to inhibit spontaneous and gonadotropin-primed ovulation in many species (4). Prostaglandin E 2 (PGE 2 ), a dominant prostanoid in the ovary, can reverse the inhibitory effect of aspirin-like drugs, when administered simultaneously. These results suggest that some of the steps of ovulation are mediated by this prostanoid (5). Indeed, luteinizing hormone surge leads to high expression of COX-2 in granulosa cells (6, 7), and a large amount of PGE 2 is produced and released into the antral fluid (8). Recently, the importance of prostanoids in early pregnancy has been definitely shown in mice deficient in COX-2. The COX-2 Ϫ͞Ϫ animals showed a reduction in ovulation number and severe failure in fertilization as well as defects in the ability of the uterus to receive implants and to undergo decidualization (9). The result that not only ovulation but fertilization was also severely affected indicates that prostanoids play a role in one of a series of preovulatory processes that are required for both ovulation and fert...