title: 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.
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.|School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, United States.
authors.forename: Wipawee
authors.identifier: http://orcid.org/0000-0002-5196-8471
authors.initials: W
authors.lastname: Winuthayanon
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.
authors.forename: Miranda L
authors.identifier: http://orcid.org/0000-0001-5424-5685
authors.initials: ML
authors.lastname: Bernhardt
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Padilla-Banks
authors.affiliation: Comparative Medicine Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.
authors.forename: Page H
authors.initials: PH
authors.lastname: Myers
authors.affiliation: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, USA.
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.
authors.forename: Sylvia C
authors.identifier: http://orcid.org/0000-0001-7713-0805
authors.initials: SC
authors.lastname: Hewitt
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, United States.
authors.forename: Carmen J
authors.identifier: http://orcid.org/0000-0001-6440-7086
authors.initials: CJ
authors.lastname: Williams
mesh_terms: D000818:Animals; D020964:Embryo Loss; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000235:genetics; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005306:Fertilization; D055785:Gene Knockdown Techniques; D051379:Mice; D010057:Oviducts / Q000187:drug effects / Q000502:physiology*; D010447:Peptide Hydrolases / Q000378:metabolism*; D015398:Signal Transduction; D014599:Uterus / Q000187:drug effects / Q000502:physiology
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D010447:Peptide Hydrolases
keywords: developmental biology; estrogen receptor; fertilization; innate immunity; mouse; oviduct; preimplantation embryo; stem cells