Oviductal estrogen receptor α signaling prevents protease-mediated embryo death

Abstract

Development of uterine endometrial receptivity for implantation is orchestrated by cyclic steroid hormone-mediated signals. It is unknown if these signals are necessary for oviduct function in supporting fertilization and preimplantation development. Here we show that conditional knockout (cKO) mice lacking estrogen receptor α (ERα) in oviduct and uterine epithelial cells have impaired fertilization due to a dramatic reduction in sperm migration. In addition, all successfully fertilized eggs die before the 2-cell stage due to persistence of secreted innate immune mediators including proteases. Elevated protease activity in cKO oviducts causes premature degradation of the zona pellucida and embryo lysis, and wild-type embryos transferred into cKO oviducts fail to develop normally unless rescued by concomitant transfer of protease inhibitors. Thus, suppression of oviductal protease activity mediated by estrogen-epithelial ERα signaling is required for fertilization and preimplantation embryo development. These findings have implications for human infertility and post-coital contraception.In female mammals, eggs made in the ovaries travel to the uterus via tubes called oviducts (or Fallopian tubes). If sperm fertilize these eggs on the way, they complete this journey as early embryos and then implant into the wall of the uterus. As sperm and then newly fertilized embryos travel down these tubes, they encounter fluid inside the oviduct, which is generated by the cells that line the tube.The hormonal changes that occur with the menstrual cycle alter the complexity and cellular composition of the uterus. When an egg is fertilized, further changes in the levels of the hormones, estrogen and progesterone, ensure the uterus becomes receptive to the embryo. However, it remains unknown whether such hormone-mediated signals also regulate the oviduct to support fertilization and early embryo development.To investigate this question, Winuthayanon et al. studied female mice that lack an important estrogen receptor in the cells that line their oviducts and uterus. These mice are infertile. This is partly because most sperm become stuck in the uterus and fail to reach the eggs in the oviduct in order to fertilize them. The oviduct also becomes a hostile environment for both eggs and embryos, as reflected in damaged eggs and the complete loss of all new embryos by two days after fertilization. These embryos die, not because their development fails, but because their outer membrane becomes damaged and breaks apart. Winuthayanon et al. showed that this is due to the persistence of enzymes that form part of the immune system inside the oviduct. These enzymes can degrade proteins and damage cell membranes.The presence of this estrogen receptor on the inner lining of the oviduct thus appears to be crucially important for reproduction (these effects were not seen when it is removed from other cells of the oviduct). The loss of this receptor also reveals the vital role that estrogen plays in suppressing parts of the immune response to ensure the oviduct provides a supportive environment for fertilization and embryo development. These findings could also have future application in the development of new contraceptives and might also shed light on the causes of human infertility.