Kisspeptin signaling in oocytes is compulsory for ovulation in adult mice

Abstract

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 Gpr54loxP/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 InformationFiDiPro programme of Academy of Finland and Sigrid Juselius foundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

GABAB Receptor Antagonism from Birth to Weaning Permanently Modifies <b><i>Kiss1</i></b> Expression in the Hypothalamus and Gonads in Mice

“…Various actions of the local Kiss1 / Kiss1r system have been described, in general proposing a positive action of kisspeptin on follicular and oocyte development [28, 75]. Recently, Ruohonen et al [76] generated a conditional oocyte-specific Gpr54 -deficient mouse line ( OoGpr54 − / − ). Puberty onset in OoGpr54 − / − females was normal, and as adults they showed unaltered basal gonadotropin levels.…”