A KiSS to remember

doi:10.1016/j.tem.2005.06.005

Trends in Endocrinology & Metabolism

Volume 16, Issue 6, August 2005, Pages 249-250

https://doi.org/10.1016/j.tem.2005.06.005 Get rights and content

The Kiss1 gene encodes a family of neuropeptides named kisspeptins, which bind to a (former orphan) G-protein-coupled receptor called GPR54. Recent investigations suggest that kisspeptins play a vital role in regulating the secretion of gonadotropin-releasing hormone (GnRH). New evidence confirms that kisspeptins act through GPR54 to stimulate GnRH secretion. Kisspeptins and GPR54 are crucial for pubertal maturation in the primate. Kiss1 mRNA is differentially regulated by sex steroids in distinct hypothalamic nuclei.

Section snippets

New candidates for the regulation of gonadotropin-releasing hormone secretion

Reproductive endocrinologists stay up late wondering how sex steroids and environmental cues converge in the forebrain to govern the activity of the few thousand gonadotropin-releasing hormone (GnRH) neurons. Recently, a family of neuropeptides and their receptor – already familiar to cancer researchers – jumped on to the center stage of reproductive science. Kisspeptins are encoded by a gene with the irresistible name of Kiss1. The receptor (or at least one of the receptors) for kisspeptins is

Kisspeptins stimulate the reproductive axis

In 2003, three teams of investigators discovered that mutations in GPR54 lead to a complete impairment of reproductive function in humans and in mice 8, 9, 10. Subsequently, several groups demonstrated that kisspeptins stimulate GnRH-mediated gonadotropin secretion – and do so at astonishingly low doses and for prolonged periods of time 7, 11, 12. Neuroendocrinologists then wondered whether the effect of kisspeptin is mediated by GPR54 or if kisspeptins signal through other, unidentified

Puberty: is a KiSS enough?

Is it conceivable that the onset of puberty is gated by the awakening of a functional connection between KiSS-1 neurons and GPR54 expressed on GnRH neurons? If this were the case, an increase in KiSS-1 neuronal activity or increased sensitivity of GnRH neurons to kisspeptins could be responsible for increased GnRH release at pubertal onset. Some evidence consistent with this model derives from a recent study by Shahab et al. [3] and from an earlier study by Navarro et al. [6]. Shahab et al.

A link between sex steroids and GnRH secretion?

Recent literature suggests that kisspeptins and GPR54 might also be important for maintaining normal reproductive function in the adult. It has long been known that sex steroids exert negative feedback effects on GnRH secretion in males and that they exert both positive and negative feedback effects in females 15, 16. However, the identity of the cells that relay these signals to GnRH neurons remains a mystery. Recently, Smith et al. [4] postulated that these cells might be KiSS-1 neurons.

Acknowledgements

We thank Heather Dungan, Michelle Gottsch, and Kathy Lee for critical reviews of the manuscript.

References (16)

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Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat
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The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system
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Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54
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Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates
Proc. Natl. Acad. Sci. U. S. A.
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Smith, J.T. et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse....
V.M. Navarro
Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54
J. Physiol.
(2004)

There are more references available in the full text version of this article.

Cited by (13)

Prenatal exposure of female mice to perﬂuorononanoic acid delays pubertal activation of the reproductive endocrine axis through enhanced hepatic FGF21 production
2021, Chemosphere
The developmental toxicity of perﬂuorononanoic acid (PFNA), a ubiquitous environmental contaminant, has been associated with the activation of PPARα. This study investigated influence of prenatal exposure to PFNA in pubertal activation of reproductive endocrine axis in female mice and explored underlying molecular mechanisms. Herein, we show that when PFNA (3 mg kg⁻¹ body weight) was orally administered during gestational days 1–18, dams showed an increase in liver weight and hepatic FGF21 synthesis via PPARα activation, and their female offspring (PFNA mice) showed an increase in liver weight and hepatic FGF21 synthesis from postnatal day (PND) 1 to PND21, which were corrected by the administration of the PPARα antagonist GW6471 from PND1-14 (pup-GW). Expression of vasopressin (VAP) in the hypothalamic suprachiasmatic nucleus (SCN) was reduced in PND14-30 PFNA mice, and could be rescued by pup-GW. Pubertal activation of kisspeptin neurons in anteroventral periventricular nucleus (AVPV) and hypothalamic GnRH neurons in PND21-30 PFNA mice was obviously suppressed, but were recovered by pup-GW or PND21-30 application of VAP. The times of vaginal opening and first estrus were delayed in PFNA mice with a decrease in ovary size and the numbers of primary, secondary and antral follicles, and corpora lutea, which were relieved by pup-GW or application of VAP. The findings indicate that prenatal exposure to PFNA through increased FGF21 production in postnatal female offspring impedes postnatal activation of SCN-VAP neurons, which suppresses pubertal onset in AVPV-kisspeptin neurons and reproductive endocrine axis, leading to delayed puberty and dysfunction of ovaries.
Polymorphism identification in ovine KISS1R/GPR54 gene among pure and crossbreeds of Iranian sheep
2019, Small Ruminant Research
Citation Excerpt :
Kisspeptins are extremely intense elicitors of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion in various mammalian species (retrieved from El-Tarabany et al., 2017). This pathway has been considered as a key gatekeeper of pubertal development and reproductive function in mammals (Popa et al., 2005). Moreover, polymorphisms of KISS1R/GPR54 gene are reported in association with precocious or late sexual maturity traits in Chinese (Feng et al., 2009; Cao et al., 2011) and Indian goat breeds (Ahlawat et al., 2015).
Fertility traits have the greatest financial impact on sheep production. In this study we aimed to characterize polymorphisms of the KISS1 receptor gene (KISS1R), also known as the G-protein-coupled receptor 54 gene (GPR54) that is reported to be involved in the control of puberty and reproductive function. Genomic DNA were obtained from 156 ewes of pure Mehraban and Shal Iranian native sheep and their crossbreeds with Romanov. The exploration of polymorphisms of the KISS1R/GPR54 gene (GenBank No: HM135393.1) was performed by single-strand conformation polymorphism analysis (SSCP) and Sanger sequencing. Seven single-nucleotide polymorphisms (SNPs) including g.396 T > G, g.456 T > C, g.475C > A, g.571 A > C, g.3431C > A, g.4108 G > A and g.4123C > A, were observed in the four breeds. Among these SNPs the g.3431C > A in the exon 4 was the only amino acid altering variant (p.195 Phe > Leu). Subsequent statistical analysis revealed that the minor A allele at this position had a significant (P < 0.01) negative effect on litter size (LS) and birth weight (BW) and could be considered as a causal mutation impairing these traits. No significant (P> 0.05) allelic association with the studied traits was found at the position g.396 T > G, g.456 T > C, g.475C > A and g.571 A > C. In contrast, carrier ewes of the SSCP pattern F (homozygous reference; g.4108 G/G, g.4123 C/C) showed a significantly (P < 0.01) higher LS than ewes carrying the patterns G (heterozygous; g.4108 G/A, 4123 C/A) or E (homozygous variant; g.4108 A/A, g.4123 C/C). The results of the present study provide additional evidences on the potential role of the KISS1R/GPR54 gene in controlling reproductive traits and particularly prolificacy in sheep.
Association analysis of polymorphisms in caprine KiSS1 gene with reproductive traits
2014, Animal Reproduction Science
Citation Excerpt :
Kisspeptins are the peptide products of KiSS1 gene, which operate via their cognate receptors, G-protein-coupled receptor (GPR54). These neuropeptides have emerged as essential upstream regulators of neurons that reside in the basal forebrain and produce Gonadotropin Releasing Hormone (GnRH) (Popa et al., 2005; Knoll et al., 2013). Human KiSS1 gene maps to chromosome 1q32 and consists of three exons (West et al., 1998; Luan et al., 2007).
KiSS1 is considered to be a key mediator of molecular mechanism of reproduction (puberty and prolificacy) in mammals. Kisspeptins are a family of structurally related peptides, encoded by KiSS1 gene, with ability to regulate gonadotropin-releasing hormone and hence hypothalamic–pituitary–gonadal axis. The present study investigated the polymorphism of caprine KiSS1 gene in 9 Indian goat breeds differing in sexual precocity and prolificacy. Comparison of KiSS1 amplified sequences of indigenous goats resulted in identification of nine SNPs (intron (1) G296C, T455G, T505A, T693C, T950C and intron (2) T1125C, A2510G, C2540T, A2803G) of which four are novel. These loci were not segregating together (r² < 0.33). Mutations existed in both, sexually precocious and late-maturing goat breeds as well as low and high prolificacy goat breeds. Three loci reported to be associated with goat litter size (G296C, G2510A and C2540T) were identified in Indian goats as well. Association between loci of KiSS1 gene and age of puberty as well as litter size was explored in Black Bengal (N = 158), a sexually precocious and prolific goat breed of India by designing PCR–RFLP. None of the mutations were found to be associated with reproductive traits however, difference in litter size as well age of sexual maturity for different genotypes indicates that the study on additional data based on more number of breeds and animals would be interesting to perform. Considering the importance of the reproductive trait in small ruminants, the results extend the limited information on genetic variation of the caprine KiSS1, which might contribute toward molecular breeding to enhance productivity of goat.
Expression of kisspeptins and their Receptors, gnrh-1/gnrhr-II-1a and gonadotropin genes in the brain of adult male and female European sea bass during different gonadal stages
2013, General and Comparative Endocrinology
Citation Excerpt :
Studies in mammals have also revealed that steroids mediate the regulation of kiss1 mRNA expression in the brain of rodents (Smith et al., 2005) and primates (Shibata et al., 2007). Recent investigations have recognized that the kisspeptin-GPR54 signaling pathway can be the putative relevant link between sex steroids and GnRH secretion as kisspeptins have been shown to play a key role in steroidal control of GnRH secretion in mammals (Popa et al., 2005). Also, it is known that Kiss1 mRNA is differentially regulated by sex steoids in distinct hypothalamic nuclei.
Kisspeptins play a critical role in the control of hypothalamic-gonadotropic function and puberty onset in mammals. Studies in fish have all supported the hypothesis that they might play similar roles in the reproduction of this animal group, however, their physiological relevance in the occurrence of key reproductive events still remains to be determined. This study examines the relative mRNA expression profiles of the duplicate kisspeptin system (kiss1, kiss2, gpr54-1b, and gpr54-2b) in the hypothalamus and pituitary of adult male and female sea bass (Dicentrarchus labrax L.) during different gonadal stages using qRT-PCR. We also report the changes in the expression levels of gnrh-1, gnrhr-II-1a, fshβ, and lhβ and the relationships observed between both kisspeptin and GnRH systems. Our data show clear sex differences in the dynamics of kisspeptin and kisspeptin receptor gene expression in the hypothalamus of sea bass during gonadal development. Overall, all four kisspeptin system genes increased either before or during the advanced stages of oogenesis and declined during atresia, exhibiting profiles that are identical to those observed for gnrhr-II-1a, fshβ, lhβ, and the gonadosomatic index (GSI). While the situation was not as clear in males, the high kiss2 expression levels observed in the hypothalamus during mid recrudescence suggest that it might be playing a role in the neuroendocrine signaling that regulates germ cell proliferation at the testicular level. In this sense, the proposed role attributed to kisspeptins as key factors in the onset of reproduction in fish receives an additional support from the data obtained in the present work. Nevertheless, further research is required to clarify their precise role in sea bass.
The kiss-1-kisspeptin-gpr54 complex: A critical modulator of GnRH neurons during pubertal activation
2010, Journal of Applied Biomedicine
Citation Excerpt :
Thereafter, both follicular development and maturation occur, under FSH stimulation (Apter 1997, Suttie et al. 1998, Aparicio 2005). The hypothalamic gene KiSS1, encodes a 54 amino acid precursor that is cleaved to a family of peptides known as kisspeptins, also known as metastin, (Popa et al. 2005, Brown et al. 2008) and has been considered as an essential integrator of peripheral cues including the gonadal steroids as well as nutritional status, which act, in turn, upon the activation of GnRH neurons (Aparicio 2005, Popa et al. 2005, Tena-Sempere 2006 a, b, c). Kisspeptin and its receptor GPR54 which is linked to G-proteins, have emerged as key elements in the regulation of GnRH secretion (Aparicio 2005, Gottsch et al. 2006, Tena-Sempere 2006a, b, c, DiVall and Radovick 2009).
Establishment of the hypothalamic-hypophyseal-gonadal function is dependent on the highly controlled and dynamic interactions between regulatory signals from the brain, pituitary and gonads, all of them leading to the attainment of reproductive capacity, where a coordinated and timely activation of GnRH neurons must occur. The GnRH neurons extend their neurosecretory axons to the hypothalamus where GnRH is released into the pituitary portal vessels to elicit the secretion of LH and FSH, which in turn, will promote gonadal development and support reproductive physiology. Genetic studies have demonstrated that disabling mutations and targeted deletions of the G-protein-coupled receptor (GPR54) generated hypogonadotropic hypogonadism. This link between GPR54 and reproduction, generated attention to the natural ligands of the GPR54 receptor, known as kisspeptins, which are translational products of the hypothalamic gene KiSS1. Recent advances in kisspeptin research have defined a major role of this molecule in controlling the onset of the reproductive function observed at puberty. The aim of this review is to highlight the basic endocrine and genetic concepts involved in the establishment of the hypothalamic-hypophyseal-gonadal axis function which promotes the onset of the reproductive function during puberty. The review highlights what is currently known about the kisspeptin-GPR54 signalling system in the activation of the GnRH neurons.
GPR54 and rGnRH I gene expression during the onset of puberty in Nile tilapia
2008, General and Comparative Endocrinology
Citation Excerpt :
Importantly, new evidence linking for the first time the Kiss1/GPR54 system and photoperiod has been reported in the hamster (Revel et al., 2006a). Many comprehensive reviews have recently been published (Colledge, 2004; Popa et al., 2005; Seminara, 2005; Aparicio, 2005; Murphy, 2005; Tena-Sempere, 2006; Kuohung and Kaiser, 2006; Smith et al., 2006a,b; Roa and Tena-Sempere, 2007; Roa et al., 2007). However, although the importance of this new system is without any doubt of prime importance, expression data in teleosts has been to date very scarce with only, to our knowledge, two published papers reporting studies performed in two seasonal marine species, the cobia (Rachycentron canadum) and grey mullet (Mugil cephalus).
The Kiss1/GPR54 system has recently been shown to play a key role in the onset of puberty in mammals. Growing evidence suggests that this system is also conserved across vertebrates although very few studies so far have been performed in lower vertebrates. The aims of this study were firstly in the teleost Nile tilapia to screen tissues for GPR54 expression levels, secondly to measure the expression patterns of GPR54 and GnRH I receptor (rGnRH I) in whole brains during the onset of puberty and finally to determine the effects of continuous illumination (LL) on receptor expression levels. Results confirmed that GPR54 was predominantly expressed in the brain and pituitary of adult tilapia. Furthermore, a significant increase of GPR54 gene expression was found in tilapia brains at 11 weeks post hatch (wph) followed by rGnRH I at 13 wph just prior to the histological observation of vitellogenic oocytes and active spermatogenesis in ova and testes at 17 wph. These results suggest a correlation between the increase of GPR54 expression in the brain and the onset of puberty. Finally, a significant effect of LL was observed on GPR54 expression levels which were characterized by a delayed surge with significantly lower levels than those of control fish. The current study not only suggests a link between the Kiss1/GPR54 system and the onset of puberty in a tropical batch spawning teleost that would be a highly conserved feature across vertebrates but also that the transcriptional mechanisms regulating GPR54 expression could be directly or indirectly influenced by light.

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Trends in Endocrinology & Metabolism

Research FocusA KiSS to remember

Section snippets

New candidates for the regulation of gonadotropin-releasing hormone secretion

Kisspeptins stimulate the reproductive axis

Puberty: is a KiSS enough?

A link between sex steroids and GnRH secretion?

Acknowledgements

Trends Endocrinol. Metab.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Horm. Behav.

Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54

Proc. Natl. Acad. Sci. U. S. A.

Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates

Proc. Natl. Acad. Sci. U. S. A.

Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54

J. Physiol.

Research Focus
A KiSS to remember