Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion.

Department of Physiology and Biophysics, Health Sciences Building, G-424, School of Medicine, University of Washington, Box 357290, Seattle, Washington 98195-7290, USA.
Endocrinology (Impact Factor: 4.72). 04/2006; 147(3):1154-8. DOI: 10.1210/en.2005-1282
Source: PubMed

ABSTRACT The Kiss1 gene encodes a family of peptides called kisspeptins, which bind to the G protein-coupled receptor GPR54. Kisspeptin(s) and its receptor are expressed in the forebrain, and the discovery that mice and humans lacking a functional GPR54 fail to undergo puberty and exhibit hypogonadotropic hypogonadism implies that kisspeptin signaling plays an essential role in reproduction. Studies in several mammalian species have shown that kisspeptins stimulate the secretion of gonadotropins from the pituitary by stimulating the release of GnRH from the forebrain after the activation of GPR54, which is expressed by GnRH neurons. Kisspeptin is expressed abundantly in the arcuate nucleus (Arc) and the anteroventral periventricular nucleus (AVPV) of the forebrain. Both estradiol and testosterone regulate the expression of the Kiss1 gene in the Arc and AVPV; however, the response of the Kiss1 gene to these steroids is exactly opposite between these two nuclei. Estradiol and testosterone down-regulate Kiss1 mRNA in the Arc and up-regulate its expression in the AVPV. Thus, kisspeptin neurons in the Arc may participate in the negative feedback regulation of gonadotropin secretion, whereas kisspeptin neurons in the AVPV may contribute to generating the preovulatory gonadotropin surge in the female. Hypothalamic levels of Kiss1 and GPR54 mRNA increase dramatically at puberty, suggesting that kisspeptin signaling could mediate the neuroendocrine events that trigger the onset of puberty. Together, these observations demonstrate that kisspeptin-GPR54 signaling in the brain serves as an important conduit for controlling GnRH secretion in the developing and adult animal.

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    ABSTRACT: Kisspeptin has been recognized as a key regulator of GnRH secretion during puberty and adulthood, conveying the feedback influence of endogenous gonadal steroids onto the GnRH system. Understanding the functional roles of this peptide depends on knowledge of the anatomical framework in which it acts, including the location of kisspeptin-expressing cells in the brain and their connections. In this paper, we review current data on the anatomy of the kisspeptin neuronal network, including its colocalization with gonadal steroid hormone receptors, anatomical sites of interaction with the GnRH system, and recent evidence of neurochemical heterogeneity among different kisspeptin neuronal populations. Evidence to date suggests that kisspeptin cells in mammals comprise an interconnected network, with reciprocal connections both within and between separate cell populations, and with GnRH neurons. At the same time, there is more functional and anatomical heterogeneity in this system than originally thought, and many unanswered questions remain concerning anatomical relationships of kisspeptin neurons with other neuroendocrine and neural systems in the brain.
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    ABSTRACT: KNDy (kisspeptin/neurokinin B/dynorphin) neurons of the arcuate nucleus (ARC) appear to mediate the negative feedback actions of estradiol and are thought to be key regulators of pulsatile LH secretion. In the ewe, KNDy neurons may also be involved with the positive feedback actions of estradiol (E(2)) to induce the LH surge, but the role of kisspeptin neurons in the preoptic area (POA) remains unclear. The goal of this study was to identify which population(s) of kisspeptin neurons is (are) activated during the LH surge and in response to the removal of E(2)-negative feedback, using Fos as an index of neuronal activation. Dual-label immunocytochemistry for kisspeptin and Fos was performed on sections containing the ARC and POA from ewes during the luteal phase of the estrous cycle, or before or after the onset of the LH surge (experiment 1), and from ovary-intact, short-term (24 h) and long-term (>30 d) ovariectomized (OVX) ewes in anestrus (experiment 2). The percentage of kisspeptin neurons expressing Fos in both the ARC and POA was significantly higher during the LH surge. In contrast, the percentage of kisspeptin/Fos colocalization was significantly increased in the ARC, but not POA, after both short- and long-term E(2) withdrawal. Thus, POA kisspeptin neurons in the sheep are activated during, and appear to contribute to, E(2)-positive feedback, whereas ARC kisspeptin (KNDy) neurons are activated during both surge and pulsatile modes of secretion and likely play a role in mediating both positive and negative feedback actions of E(2) on GnRH secretion in the ewe.
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    ABSTRACT: Release of gonadotropins in adult rodents is sex specific and dependent upon kisspeptin (Kiss1) neurons. This crucial pathway within the hypothalamic-pituitary-gonadal (HPG) axis is profoundly influenced by neonatal estrogens, which induce a male-like phenotype. Classically, estrogen activity is mediated via the estrogen receptors α and β (ERα and ERβ), but the relative roles each plays in organizing the sex-specific ontogeny of kisspeptin signaling pathways remain unresolved. Thus, the present study used in situ hybridization histochemistry (ISHH) to map the temporal and sexually dimorphic neonatal mRNA expression profiles of ERα, ERβ, and Kiss1 in the anterioventral periventricular nucleus (AVPV), medial preoptic area (MPOA), ventromedial nucleus (VMN), and arcuate nucleus (ARC), all regions critical for kisspeptin regulation of gonadotropin secretion. In general, females had higher levels of ERα, in all regions examined, a sex difference that persisted until postnatal day (PND) 19 except in the ARC. Males had significantly more ERβ expression in the AVPV at birth, but this sex difference was lost and then re-emerged on PND 19, with females having more than males. VMN ERβ levels were higher in females until PND 19. Kiss1 was not detectable until PND 11 in the anterior hypothalamus, but expression levels were equivalent at birth in the ARC. By PND 2, ARC ERα and Kiss1 levels were abundant, sexually dimorphic (higher in females), and, respectively, showed a U- and a bell-shaped pattern with age. Sex differences in ARC Kiss1 expression provide evidence that Kiss1 may play a role in the sexual dimorphic organization of the neonatal brain. These detailed profiles of neonatal Kiss1 and ERs mRNA levels will help elucidate the relative roles each plays in the sex-specific, estrogen-dependent organization of gonadotropin signaling pathways.
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