title: Implantation failure in female Kiss1-/- mice is independent of their hypogonadic state and can be partially rescued by leukemia inhibitory factor.
abstract: The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss of Kiss1 in the mouse results in infertility, a condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that in Kiss1(-/-) female mice, acute replacement of gonadotropins and estradiol restores ovulation, mating, and fertilization; however, these mice are still unable to achieve pregnancy because embryos fail to implant. Progesterone treatment did not overcome this defect. Kiss1(+/-) embryos transferred to a wild-type female mouse can successfully implant, demonstrating the defect is due to maternal factors. Kisspeptin and its receptor are expressed in the mouse uterus, and we suggest that it is the absence of uterine kisspeptin signaling that underlies the implantation failure. This absence, however, does not prevent the closure of the uterine implantation chamber, proper alignment of the embryo, and the ability of the uterus to undergo decidualization. Instead, the loss of Kiss1 expression specifically disrupts embryo attachment to the uterus. We observed that on the day of implantation, leukemia inhibitory factor (Lif), a cytokine that is absolutely required for implantation in mice, is weakly expressed in Kiss1(-/-) uterine glands and that the administration of exogenous Lif to hormone-primed Kiss1(-/-) female mice is sufficient to partially rescue implantation. Taken together, our study reveals that uterine kisspeptin signaling regulates glandular Lif levels, thereby identifying a novel and critical role for kisspeptin in regulating embryo implantation in the mouse. This study provides compelling reasons to explore this role in other species, particularly livestock and humans.
authors.affiliation: The Children's Health Research Institute (M.C., M.P., A.E., C.G.-M., N.G.B., A.J.W., A.V.B.), Lawson Health Research Institute (M.C., M.P., A.E., C.G.-M., N.G.B., A.J.W., A.V.B.), and Department of Obstetrics and Gynaecology (M.C., M.P., A.J.W., A.V.B.), London, Ontario, Canada N6C 2V5; Harvard Reproductive Endocrine Sciences Center (Y.-M.C., C.C., S.B.S.), Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology (Y.-M.C.), Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115; Department of Obstetrics and Gynecology and Reproductive Sciences (R.R.), University of Vermont College of Medicine, Burlington, Vermont 05405; and Departments of Paediatrics (A.E., N.G.B.), Biochemistry (A.E., N.G.B.), Physiology and Pharmacology (M.N., M.B., A.J.W., A.V.B.), and Oncology (M.B.), The University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Michele
authors.initials: M
authors.lastname: Calder
authors.forename: Yee-Ming
authors.initials: YM
authors.lastname: Chan
authors.forename: Renju
authors.initials: R
authors.lastname: Raj
authors.forename: Macarena
authors.initials: M
authors.lastname: Pampillo
authors.forename: Adrienne
authors.initials: A
authors.lastname: Elbert
authors.forename: Michelle
authors.initials: M
authors.lastname: Noonan
authors.forename: Carolina
authors.initials: C
authors.lastname: Gillio-Meina
authors.forename: Claudia
authors.initials: C
authors.lastname: Caligioni
authors.forename: Nathalie G
authors.initials: NG
authors.lastname: Bérubé
authors.forename: Moshmi
authors.initials: M
authors.lastname: Bhattacharya
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Watson
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
authors.forename: Andy V
authors.initials: AV
authors.lastname: Babwah
mesh_terms: D000818:Animals; D010064:Embryo Implantation; D004958:Estradiol / Q000502:physiology; D005260:Female; D006062:Gonadotropins / Q000502:physiology; D059648:Kisspeptins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053605:Leukemia Inhibitory Factor / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D011374:Progesterone / Q000378:metabolism; D013480:Superovulation; D014599:Uterus / Q000502:physiology*
chemical_list: D006062:Gonadotropins; C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D011374:Progesterone; D004958:Estradiol