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Kisspeptin signaling in oocytes is compulsory for ovulation in adult mice
Author(s) -
Ruohonen Suvi T,
Gaytan Francisco,
Gaudi Andrea Usseglio,
Franssen Delphine,
Ohlsson Claes,
Poutanen Matti,
TenaSempere Manuel
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.580.5
Subject(s) - anovulation , kisspeptin , biology , ovulation , endocrinology , medicine , estrous cycle , folliculogenesis , ovary , bone morphogenetic protein 15 , growth differentiation factor 9 , polycystic ovary , hypothalamus , gene , genetics , hormone , insulin , embryogenesis , insulin resistance , bone morphogenetic protein 7 , bone morphogenetic protein
Kisspeptins, encoded by the Kiss1 gene, are crucial brain factors for the control of reproduction, with an essential role in the generation of the pre‐ovulatory surge of gonadotropins and, hence, ovulation. Yet, kisspeptins are also found in peripheral reproductive organs and their receptor, Gpr54, is expressed in various target tissues, including the ovary, where its physiological role remains contentious. Global Gpr54 −/− mice are hypogonadotropic and infertile; female null mice display disrupted folliculogenesis and anovulation. However, despite the predominant brain actions of kisspeptins, how much of this phenotype is due to local, and not central, kisspeptin signaling deficiency remains unknown. To address this, we generated a conditional oocyte‐specific Gpr54 deficient mouse line ( OoGpr54 − / − ), by crossing Gdf9 ‐Cre + mice with Gpr54 loxP/loxP mice. The efficacy of Gdf9 ‐promoter to drive the expression of Cre in oocytes was verified by a breeding test, and the Gpr54 depletion from oocytes was confirmed with RT‐qPCR. At the time of pubertal transition, OoGpr54 − / − females were indistinguishable from their wiltype controls with preserved puberty onset. However, already at 2 months of age, 45% of OoGpr54 −/− females showed histological features reminiscent of ovarian failure, with presence of large atretic antral follicles and absence of corpora lutea as an index of anovulation. These features were also associated with disrupted estrous cyclicity characterized by an increase in the length of the estrus phase of the uterine cycle. Penetrance of this phenotype progressed with age, with 55% of OoGpr54 −/− females at 3–4 months, 80% at 6 months and 100% at 10 months displaying features of complete premature ovarian insufficiency (POI). In addition, 4‐month‐old OoGpr54 −/− female mice displaying POI showed decreased serum estradiol and progesterone levels, yet sustained Gpr54 expression in the hypothalamus and unaltered basal gonadotropin levels. Ovarian RNASeq analyses revealed global changes in expression profiles in OoGpr54 −/− mice, including genes involved in cellular communication, steroidogenesis and intracellular signaling pathways. Finally, the anovulatory state of OoGpr54 −/− mice was rescued by exogenously administered gonadotropin priming, and was largely prevented by early onset consecutive pregnancies, although multiparous OoGpr54 −/− dams showed a slight decrease in fecundity. Our results pinpoint the important role of oocyte kisspeptin signaling in the direct control of ovulation, whose deregulation may also be an underlying cause for POI in women. Support or Funding Information FiDiPro programme of Academy of Finland and Sigrid Juselius foundation This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .