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Reproductive Biology and Endocrinology

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Open Access 01-12-2015 | Short communication

The pregnant mouse uterus exhibits a functional kisspeptin/KISS1R signaling system on the day of embryo implantation

Authors: Mehri Fayazi, Michele Calder, Moshmi Bhattacharya, George A. Vilos, Stephen Power, Andy V. Babwah

Published in: Reproductive Biology and Endocrinology | Issue 1/2015

Abstract

Background

Expression of kisspeptin (protein) and Kiss1r (mRNA) was recently documented in the mouse uterus on D4 of pregnancy (the day of embryo implantation) suggesting that the uterine-based kisspeptin (KP)/kisspeptin receptor (KISS1R) signaling system regulates embryo implantation. Despite this important suggestion, it was never demonstrated that the uterus actually exhibits a functional KP/KISS1R signaling system on D4 of pregnancy. Thus, the goal of this study was to determine whether a functional KP/KISS1R signaling system exists in the mouse uterus on D4 of pregnancy.

Findings

Since kisspeptin/KISS1R signaling triggers the phosphorylation of the mitogen-activated protein kinases p38 and ERK1/2, through immunohistochemical analyses, we determined whether exogenously administered kisspeptin could trigger p38 and ERK1/2 phosphorylation in the uterus on D4 of pregnancy. The results clearly demonstrated that kisspeptin could and that its effects were mediated via KISS1R. Additionally, the robust kisspeptin-triggered response was observed in the pregnant uterus only. Finally, it was demonstrated that on D4 of pregnancy the Kiss1 null uterus expresses functional KISS1R molecules capable of mediating the effects of kisspeptin.

Conclusions

These results lead us to conclude that on D4 of pregnancy, the mouse uterus expresses a functional KP/KISS1R signaling system strengthening the possibility that this signaling system regulates embryo implantation. These findings strengthen the rationale for determining whether such a functional system exists in the uterus of the human female and if so, what role it might play in human pregnancy.

Kirilov M, Clarkson J, Liu X, Roa J, Campos P, Porteous R, et al. Dependence of fertility on kisspeptin-Gpr54 signaling at the GnRH neuron. Nat Commun. 2013;4:2492.CrossRefPubMed

Novaira HJ, Momodou LS, Hoffman G, Koo H, Ko C, Wolfe A, et al. Disrupted Kisspeptin Signaling in GnRH Neurons Leads to Hypogonadotrophic Hypogonadism. Mol Endocrinol. 2014;28:225–38.PubMedCentralCrossRefPubMed

Millar RP, Babwah AV. KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis. Neuroendocrinology. 2015;101:193–210.CrossRefPubMed

Calder M, Chan YM, Raj R, Pampillo M, Elbert A, Noonan M, et al. Implantation failure in female Kiss1 ^−/− mice is independent of their hypogonadic state and can be partially rescued by leukemia inhibitory factor. Endocrinology. 2014;155:3065–78.PubMedCentralCrossRefPubMed

Dorfman MD, Garcia-Rudaz C, Alderman Z, Kerr B, Lomniczi A, Dissen GA, et al. Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure. Endocrinology. 2014;155:3098–11.PubMedCentralCrossRefPubMed

Gaytan F, Garcia-Galiano D, Dorfman MD, Manfredi-Lozano M, Castellano JM, Dissen GA, et al. Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion. Endocrinology. 2014;155:3088–97.CrossRefPubMed

Zhang P, Tang M, Zhong T, Lin Y, Zong T, Zhong C, et al. Expression and function of kisspeptin during mouse decidualization. PloS ONE. 2014;9:e97647.PubMedCentralCrossRefPubMed

Bhattacharya M, Babwah AV. Kisspeptin: Beyond the brain. Endocrinology. 2015;156:1218–27.CrossRefPubMed

Lapatto R, Pallais JC, Zhang D, Chan Y-M, Mahan A, Cerrato F, et al. Kiss1 ^−/− mice exhibit more variable hypogonadism than Gpr54 ^−/− mice. Endocrinology. 2007;148:4927–36.CrossRefPubMed

10.

Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor KISS1R. J Biol Chem. 2001;276:34631–36.CrossRefPubMed

11.

Szereszewski JM, Pampillo M, Ahow MR, Offermanns S, Bhattacharya M, Babwah AV. GPR54 regulates ERK1/2 activity and hypothalamic gene expression in a Gα_q/11 and β-arrestin-dependent manner. PloS One. 2010;5:e12964.PubMedCentralCrossRefPubMed

12.

Ahow M, Min L, Pampillo M, Nash C, Wen J, Soltis K, et al. Kiss1r signals independently of Gα_q/11 and triggers LH secretion via the β-arrestin pathway in the male mouse. Endocrinology. 2014;155:4433–46.CrossRefPubMed

13.

ELHabazi K, Humbert JP, Bertin I, Schmitt M, Bihel F, Bourguignon JJ, et al. Endogenous mammalian RF-amide peptides, including PrRP, kisspeptin and 26RFa, modulate nociception and morphine analgesia via NPFF receptors. Neuropharmacology. 2013;75:164–71.CrossRefPubMed

14.

Roseweir AK, Kauffman AS, Smith JT, Guerriero KA, Morgan K, Pielecka-Fortuna J, et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci. 2009;29:3920–9.PubMedCentralCrossRefPubMed

15.

Liu Z, Ren C, Jones W, Chen P, Seminara SB, Chan YM, et al. LC-MS/MS quantification of a neuropeptide fragment kisspeptin-10 (NSC 741805) and characterization of its decomposition product and pharmacokinetics in rats. J Chromatogr B Analyt Technol Biomed Life. 2013;926:1–8.CrossRef

16.

Hantak AM, Bagchi IC, Bagchi MK. Role of uterine stromal-epithelial crosstalk in embryo implantation. Int J Dev Biol. 2014;58:139–46.CrossRefPubMed

Title: The pregnant mouse uterus exhibits a functional kisspeptin/KISS1R signaling system on the day of embryo implantation
Authors: Mehri Fayazi
Michele Calder
Moshmi Bhattacharya
George A. Vilos
Stephen Power
Andy V. Babwah
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Reproductive Biology and Endocrinology / Issue 1/2015
Electronic ISSN: 1477-7827
DOI: https://doi.org/10.1186/s12958-015-0105-1

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Springer Medicine

The pregnant mouse uterus exhibits a functional kisspeptin/KISS1R signaling system on the day of embryo implantation

Abstract

Background

Findings

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Findings

Conclusions

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