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Minireview: Kisspeptin Neurons as Central Processors in the Regulation of Gonadotropin-Releasing Hormone Secretion

Departments of Physiology and Biophysics (H.M.D., R.A.S.) and Obstetrics and Gynecology (D.K.C., R.A.S.), University of Washington, Seattle, Washington 98195

Address all correspondence and requests for reprints to: Robert A. Steiner, Department of Physiology and Biophysics, Health Sciences Building, G-424, School of Medicine, University of Washington, Box 357290, Seattle, Washington 98195-7290. E-mail: steiner{at}u.washington.edu.

	Abstract

Top Abstract Introduction GPR54 Becomes an Adopted... Kisspeptin Stimulates GnRH... Anatomy and Regulation of... Does Puberty Begin with... Kisspeptin Neurons as Central... References

 
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.

	Introduction

Top Abstract Introduction GPR54 Becomes an Adopted... Kisspeptin Stimulates GnRH... Anatomy and Regulation of... Does Puberty Begin with... Kisspeptin Neurons as Central... References

 
THE Kiss1 GENE WAS ORIGINALLY identified by scientists in Hershey, PA, who observed that its expression in tumor cells was restricted to cells that were apparently not metastatic (1, 2, 3). Thus, the gene was inferred to be a suppressor sequence because of its antimetastatic properties and dubbed Kiss1 in honor of another famous product of Hershey, the Hershey chocolate kiss. The Kiss1 gene encodes a 145-amino-acid protein that is enzymatically cleaved into a 54-amino-acid peptide, known as kisspeptin-54 or metastin, as well as shortened peptides of 14, 13, or 10 amino acids (4) (reviewed in Ref.5). In this review, these peptides will be collectively referred to as kisspeptin. Besides tumor cells, expression of kisspeptin has been detected in the hypothalamus and the placenta, where it may contribute to regulation of implantation (6, 7). In 2001, several groups reported that kisspeptin is a ligand of the receptor known as GPR54 (and also as OT7T175 or AXOR12) (4, 6, 8).

	GPR54 Becomes an Adopted Orphan

Top Abstract Introduction GPR54 Becomes an Adopted... Kisspeptin Stimulates GnRH... Anatomy and Regulation of... Does Puberty Begin with... Kisspeptin Neurons as Central... References

 
GPR54 was an orphan G protein-coupled receptor of unknown significance until it was discovered to have a high affinity for kisspeptin. Although this ligand and receptor pair initially seized the attention of scientists studying cancer biology, a startling revelation in 2003 exposed another important function of kisspeptin signaling through GPR54. de Roux et al. (9) and Seminara et al. (10), working independently, found that a few consanguineous families demonstrate a relatively high incidence of hypogonadotropic hypogonadism and that affected individuals within these families possess a mutation in the GPR54 gene. Similar defects were found in engineered mice bearing a loss-of-function mutation to GPR54 (GPR54 KO) (10, 11). Adult humans and mice with nonfunctional GPR54 both exhibit low plasma levels of gonadotropins and sex steroids, underdeveloped gonads, and infertility. Despite their perpetual prepubertal state, these individuals, both human and murine, are otherwise normal and apparently healthy.

These observations on the phenotype of animals lacking a functional GPR54 opened speculation about the significance of kisspeptin/GPR54 signaling in the regulation of the reproductive axis. At that point (late in 2003), it seemed reasonable to infer that kisspeptin signaling plays some sort of role in the hypothalamic pathway that controls the secretion of GnRH; however, the cellular and molecular mechanisms that mediate this phenomenon were completely unknown. Many laboratories around the world soon jumped into the fray to solve this mystery.

	Kisspeptin Stimulates GnRH Secretion

Top Abstract Introduction GPR54 Becomes an Adopted... Kisspeptin Stimulates GnRH... Anatomy and Regulation of... Does Puberty Begin with... Kisspeptin Neurons as Central... References

 
Exogenously administered kisspeptin exerts a profound stimulatory effect on gonadotropin secretion. It is now well documented that central (directly into ventricles of the brain) and peripheral administration of kisspeptin stimulates a dose-dependent rise in serum levels of LH and FSH in adult male rats (12, 13, 14, 15); moreover, these stimulatory effects can be produced in adult mice with astonishingly low central doses of kisspeptin, 1 fmol (16). Sheep, macaques, and humans also share this positive response to kisspeptin administration (17, 18, 19). Kisspeptin has no effect on gonadotropin secretion in mice lacking a functional GPR54 gene, suggesting that the facilitatory effects of kisspeptin on gonadotropins is mediated by cells that express GPR54 (17). Those cells most likely reside within either the brain or pituitary, both of which have been shown to express GPR54 (6, 13, 20, 21).

The results from a wide variety of studies indicate that kisspeptin stimulates gonadotropin secretion via a hypothalamic pathway that activates GnRH neurons. For example, acyline (a GnRH antagonist) blocks the ability of kisspeptin to stimulate gonadotropin release in the rat, mouse, and primate (16, 18, 22), and kisspeptin evokes the release of GnRH from rat hypothalamic explants (12). Kisspeptin also induces LH secretion from rat pituitary explants, suggesting that it may have a direct effect on gonadotropes (14). However, the ability of GnRH antagonists to abolish the rise in LH and FSH associated with central or peripheral kisspeptin administration indicates that the direct stimulation of the pituitary by kisspeptin is not a primary mechanism of gonadotropin secretion (14, 15, 16, 23, 24). Irwig et al. (22) further demonstrated in rats that central administration of kisspeptin induces Fos expression in GnRH neurons, indicative of neuronal stimulation. Not only does kisspeptin activate GnRH neurons, but it also appears to act directly on those neurons. In situ hybridization (ISH) techniques have revealed that many GnRH neurons in the rat and mouse also express the mRNA for GPR54 (17, 22). These observations in the mammal were presaged by the earlier work in the cichlid fish by Parhar and his colleagues (25), who used laser capture microscopy and RT-PCR assays to demonstrate that GnRH neurons in these animals coexpress GPR54 mRNA. Together, these experiments argue that kisspeptin binds to GPR54 expressed on GnRH neurons, which then directly stimulates the release of GnRH, presumably through some Ca²⁺-mediated process typical of Gq/G₁₁-coupled receptors such as GPR54 (reviewed in Refs.26 and 27). Nevertheless, unequivocal proof that kisspeptin neurons make direct synaptic contact with GnRH neurons remains to be demonstrated.

	Anatomy and Regulation of Kiss1 Expression in the Forebrain

Top Abstract Introduction GPR54 Becomes an Adopted... Kisspeptin Stimulates GnRH... Anatomy and Regulation of... Does Puberty Begin with... Kisspeptin Neurons as Central... References

 
The next step was mapping the anatomical distribution of kisspeptin neurons in the forebrain. ISH assays in mice have revealed that kisspeptin neurons (i.e. those that express Kiss1 mRNA) are most numerous in the arcuate nucleus (Arc), but significant numbers are also seen in periventricular nucleus (PeN) and the anteroventral periventricular nucleus (AVPV) (16, 28, 29). Some scattered cells in the anterodorsal preoptic area and the bed nucleus of the stria terminalis also appear to express Kiss1 mRNA. Although both sexes express Kiss1 mRNA in all five areas, expression in the AVPV is sexually dimorphic, where the expression of Kiss1 mRNA is much greater in females. This finding is not surprising considering that the AVPV in females is larger by volume and contains more neurons than the AVPV of males (30).

The Arc and AVPV have long been thought to play important roles in the feedback regulation of GnRH and gonadotropin secretion by estradiol (E) and testosterone (T); however, the circuitry that mediates this phenomenon remains ambiguous (31). Evidence from two independent groups of investigators suggests that kisspeptin neurons could be responsible for mediating the negative feedback effects of sex steroids on GnRH secretion. First, Navarro et al. (13) used whole-hypothalamus RT-PCR to demonstrate the inhibitory effect of E on Kiss1 expression in the female rat. Thereafter, in two ISH-based investigations, one in male and the other in female mice, Smith and coworkers (28, 29) found that reduction of circulating levels of sex steroids by gonadectomy increased the number of detectable Kiss1 mRNA-expressing neurons as well as the content of Kiss1 mRNA per cell in the Arc. Replacement of T in castrated males and E in ovariectomized females restored the expression of Kiss1 mRNA to that observed in intact, untreated animals. The suppression of kisspeptin activity by sex steroids in the Arc appears to be mediated by estrogen receptors (ER) in the female and both ER and androgen receptors in the male (28, 29). These findings are consistent with a role for kisspeptins in mediating the negative feedback effects of gonadal steroids on GnRH secretion in both the male and female.

Although kisspeptin neurons in the Arc have been implicated in the negative feedback of sex steroids, the results of high-resolution ISH analysis suggest that kisspeptin neurons in more rostral nuclei of the forebrain have a different agenda. The expression of Kiss1 mRNA in the PeN and AVPV of both male and female mice is positively regulated by sex steroids (28, 29). Gonadectomy produces a dramatic decrease in the number of Kiss1 mRNA-expressing cells in the AVPV. Replacement of E in gonadectomized animals restores the expression of Kiss1 mRNA to that of normal, intact animals in both sexes. T also restores Kiss1 mRNA levels in the AVPV to those of intact males, an effect that appears to depend on the aromatization of T to E (28). Furthermore, targeted disruptions of the ER gene blocks the ability of E to induce the expression of Kiss1 mRNA in the AVPV (29). Thus, the inductive effects of gonadal steroids on the expression of Kiss1 in the AVPV appear to be mediated by ER in both sexes.

The opposite effects of sex steroids on expression of Kiss1 mRNA between the AVPV and Arc beg several questions. First, how does E induce the expression of Kiss1 mRNA in the AVPV but suppress it in the Arc? Although we don’t know the answer to this question, it may be that E, acting through ER, recruits coactivators of transcription in kisspeptin neurons of the AVPV and corepressors of transcription in the Arc (32). Second, why does E up-regulate Kiss1 mRNA in the AVPV and down-regulate it in the Arc? It seems likely that kisspeptin neurons in these two areas must perform different functions, with those in the Arc being clearly implicated in the negative feedback regulation of gonadotropin secretion. Because the AVPV is thought to play a vital role in the generation of the preovulatory gonadotropin surge, it is conceivable that kisspeptin neurons in this region mediate the positive feedback effects of E on gonadotropin secretion. Evidence presented by Kinoshita et al. (20) demonstrating that a blockade of kisspeptin signaling in the female rat abolishes the preovulatory LH surge is consonant with a role in positive feedback for kisspeptin in the female. However, the notion of a positive (or inductive) feedback effect of E (and T) on Kiss1 expression in the AVPV of the male is more difficult to understand. It may be that the stimulatory effect of sex steroids in the AVPV of the male occurs as a remnant (or vestige) of the positive feedback pathway, which is mostly ablated in the developing male during the critical period of sexual differentiation (30, 33). Establishing the functional significance of the inductive effects of sex steroids on Kiss1 expression in the AVPV and PeN of both the male and female is an important objective for future research.

	Does Puberty Begin with a Kiss?

Top Abstract Introduction GPR54 Becomes an Adopted... Kisspeptin Stimulates GnRH... Anatomy and Regulation of... Does Puberty Begin with... Kisspeptin Neurons as Central... References

 
Compelling evidence from several laboratories has now established 1) centrally administered kisspeptin stimulates gonadotropin secretion through its inductive effects on GnRH neurons and 2) gonadal steroids differentially regulate the expression of Kiss1 in different populations of neurons in the forebrain. Do kisspeptin and GPR54 play a role in gating the onset of puberty? Navarro et al. (24) have reported that the chronic, central administration of kisspeptin to prepubertal female rats advances the age of vaginal opening by several days (compared with vehicle-treated rats), raising the possibility that increased kisspeptin-GPR54 signaling initiates the onset of puberty. Increased kisspeptin-GPR54 signaling could result from either increased synaptic release of kisspeptin or increased GPR54 responsiveness across pubertal development.

Evidence that kisspeptin signaling does, in fact, increase across puberty has been reported in several species. Navarro and coworkers (13) have reported that both male and female rats experience a sharp increase in the hypothalamic content of Kiss1 mRNA at the time of puberty. In the AVPV of mice, Han and colleagues (34) have found that both the number of neurons that express Kiss1 mRNA and their content of Kiss1 mRNA per cell is greater in adult compared with prepubertal animals. In addition, Kiss1 mRNA content is higher in the hypothalamus of pubertal monkeys than in juveniles of both sexes (18). The changes in the expression of hypothalamic Kiss1 mRNA found in these studies seem likely to reflect increased kisspeptin neuronal activity over pubertal development.

As in the case of Kiss1, the expression of GPR54 is also amplified over pubertal development. Hypothalamic content of GPR54 mRNA increases at puberty in the male and female rat (13). In the macaque, Shahab and his colleagues (18) observed an increase in hypothalamic content of GPR54 mRNA in intact females, but not in castrated males, suggesting that sex steroids (at least in the male) could mediate the pubertal induction of GPR54 in the macaque. As is the case of the castrated male macaque, in the hypothalamus of intact male mice, the expression of GPR54 mRNA mice does not appear to change over puberty (34), which would argue against a role of GPR54 in triggering the onset of puberty in this species. However, a recent investigation in the male mouse has revealed that kisspeptin depolarizes more than 90% of GnRH neurons from adults in vitro, but the same treatment depolarizes fewer than 30% of GnRH neurons in juveniles (34). These results would argue that despite the fact that the expression of GPR54 apparently doesn’t change with puberty, the ability of GPR54 to stimulate neuronal activity nevertheless increases over development. This idea is supported by evidence that much higher doses of kisspeptin are required to stimulate LH secretion in prepubertal compared with adult mice (34). Taken together, these observations suggest that an increase in the efficacy of the kisspeptin-GPR54 signaling accompanies the onset of puberty, although the molecular mechanisms may be species dependent. Thus, the activities of both kisspeptin and its receptor appear to ramp up during pubertal development; however, the mechanisms that initiate and sustain this process are currently unknown. Although an intact kisspeptin-GPR54 pathway appears to be a prerequisite for puberty, it is likely to be only one of many factors required to admit a juvenile into adulthood.

	Kisspeptin Neurons as Central Processors

Top Abstract Introduction GPR54 Becomes an Adopted... Kisspeptin Stimulates GnRH... Anatomy and Regulation of... Does Puberty Begin with... Kisspeptin Neurons as Central... References

 
Evidence to date suggests that kisspeptin signaling is an essential component of the neuroendocrine reproductive axis and is consistent with the hypothesis that kisspeptin neurons in the forebrain act as gatekeepers to awakening of reproduction at puberty and coordinating reproductive activity during adulthood. Kisspeptin neurons are direct targets of gonadal steroids and may be involved in both the negative and positive feedback regulation of gonadotropin secretion. A simplified model of the circuitry involved in this process is illustrated in Fig. 1. Metabolic and environmental factors are also known to play an important role in the regulation of the hypothalamic-pituitary-gonadal axis. Do kisspeptin neurons serve as serve as a cellular link between metabolism and reproduction (as shown in Fig. 2)? This possibility remains largely unexplored, but recent evidence indicates that kisspeptins may be involved in mediating at least some of the effects of the body’s metabolic status on reproduction.

View larger version (32K): [in this window] [in a new window]   FIG. 1. Kisspeptin stimulates the neuroendocrine reproductive axis, and sex steroids differentially regulate the expression of Kiss1 mRNA in different nuclei within the forebrain. Kisspeptin released by neurons in the AVPV and Arc stimulates GnRH release, which induces the release of LH and FSH. The gonads respond to gonadotropins by secreting sex steroids, which then feed back to regulate the activity of kisspeptin neurons (see text for details), inhibiting Kiss1 expression in the Arc and inducing its expression in the AVPV. The inductive effect of sex steroids on Kiss1 expression in the AVPV may contribute to the preovulatory LH surge in females (and possibly T-mediated sex behavior in the male).

View larger version (21K): [in this window] [in a new window]   FIG. 2. Kisspeptin neurons may act as central processors for relaying signals from the periphery to GnRH neurons. Metabolic and environmental factors regulate reproductive function, which ensures that reproduction proceeds only when metabolic and environmental conditions are favorable. Kisspeptin stimulates GnRH secretion, and Kiss1 mRNA is both negatively and positively regulated by sex steroids (see Fig. 1 and text for details). The expression of Kiss1 may be induced by leptin, whose plasma levels reflect the state of metabolic reserves. Kisspeptin neurons may also receive input from the hypothalamic-pituitary-adrenal axis and from environmental cues such as photoperiod via the suprachiasmatic nucleus of the hypothalamus (SCN).

Studies on the interaction of kisspeptin and GPR54 with adipocytokines and adrenal hormones may shed more light on the functioning of the hypothalamic-pituitary-gonadal axis before and after puberty. The relationship between kisspeptin and the action of other endogenous GnRH secretagogues, such as excitatory amino acids (e.g. glutamate), galanin-like peptide, and vasopressin, are worthy of exploration, because it is conceivable that the effects of these neurotransmitters on GnRH secretion are mediated through kisspeptin-GPR54 signaling. In conclusion, the kisspeptin-GPR54 pathway plays a vital role in the neuroendocrine regulation of reproduction in the male and female mammal.

	Acknowledgments

 
We thank Michelle Gottsch, Kathy Lee, and Sonya Jakawich for critical comments and suggestions on earlier versions of this manuscript.

	Footnotes

 
This work was supported by grants from the National Institutes of Health [R01 HD27142, SCCPRR (U54) HD12629, and R01 DK61517].

The authors have no potential conflicts of interest to declare.

First Published Online December 22, 2005

Abbreviations: Arc, Arcuate nucleus; AVPV, anteroventral periventricular nucleus; E, estradiol; ER, estradiol receptor; ISH, in situ hybridization; PeN, periventricular nucleus; T, testosterone.

Received October 11, 2005.

Accepted for publication November 10, 2005.

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Top Abstract Introduction GPR54 Becomes an Adopted... Kisspeptin Stimulates GnRH... Anatomy and Regulation of... Does Puberty Begin with... Kisspeptin Neurons as Central... References

 

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