The Kiss1 gene encodes a family of neuropeptides called kisspeptins, which activate the receptor G protein-coupled receptor-54 and play a role in the neuroendocrine regulation of GnRH secretion. We examined whether estradiol (E2) regulates KiSS-1 in the forebrain of the female mouse by comparing KiSS-1 mRNA expression among groups of ovary-intact (diestrus), ovariectomized (OVX), and OVX plus E2-treated mice. In the arcuate nucleus (Arc), KiSS-1 expression increased after ovariectomy and decreased with E2 treatment. Conversely, in the anteroventral periventricular nucleus (AVPV), KiSS-1 expression was reduced after ovariectomy and increased with E2 treatment. To determine whether the effects of E2 on KiSS-1 are mediated through estrogen receptor (ER)alpha or ERbeta, we evaluated the effects of E2 in OVX mice that lacked functional ERalpha or ERbeta. In OVX mice that lacked functional ERalpha, KiSS-1 mRNA did not respond to E2 in either the Arc or AVPV, suggesting that ERalpha is essential for mediating the inhibitory and stimulatory effects of E2. In contrast, KiSS-1 mRNA in OVX mice that lacked functional ERbeta responded to E2 exactly as wild-type animals. Double-label in situ hybridization revealed that virtually all KiSS-1-expressing neurons in the Arc and AVPV coexpress ERalpha, suggesting that the effects of E2 are mediated directly through KiSS-1 neurons. We conclude that KiSS-1 neurons in the Arc, which are inhibited by E2, may play a role in the negative feedback regulation of GnRH secretion, whereas KiSS-1 neurons in the AVPV, which are stimulated by E2, may participate in the positive feedback regulation of GnRH secretion.

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Regulation of Kiss1 gene expression in the brain of the female mouse.

tizable androgen, suggesting that both estrogen receptor (ER) and androgen receptor (AR) play a role in T-mediated regulation of KiSS-1. Studies of the effects of T on KiSS-1 expression in mice with either a deletion of the ER or a hypomorphicalleletotheARrevealedthattheeffectsofTaremediated by both ER and AR pathways, which was confirmed by the presence of either ER or AR coexpression in most KiSS-1 neurons in the Arc. These observations suggest that KiSS-1 neurons in the Arc, whose transcriptional activity is inhibited byT,aretargetsforthenegativefeedbackregulationofGnRH secretion, whereas KiSS-1 neurons in the anteroventral periventricular nucleus, whose activity is stimulated by T, may mediate other T-dependent processes. (Endocrinology 146: 2976–2984, 2005)

/pdf/differential-regulation-of-kiss-1-mrna-expression-by-sex-2hb487u5xm.pdf

Differential Regulation of KiSS-1 mRNA Expression by Sex Steroids in the Brain of the Male Mouse

GnRH and GnRH receptors in metazoa: a historical, comparative, and evolutive perspective.

Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus (ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17β-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptor-dependent pathways; 3) senktide, an agonist for the NKB receptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male.

/pdf/regulation-of-nkb-pathways-and-their-roles-in-the-control-of-18v1j09jwo.pdf

Regulation of NKB Pathways and Their Roles in the Control of Kiss1 Neurons in the Arcuate Nucleus of the Male Mouse

Developmental Programming and Endocrine Disruptor Effects on Reproductive Neuroendocrine Systems

Localization of gonadotropin-releasing hormone in the central nervous system and a peripheral chemosensory organ of Aplysia californica

Effects of steroid hormones on spermatogenesis and GnRH release in male Leopard frogs, Rana pipiens.

The administration of adult physiological levels of testosterone (T) and 17β-estradiol (E2) to male Siberian hamsters was previously shown to delay the onset of puberty To examine whether this is 

Jason B Lunden

Papers

Localization of gonadotropin-releasing hormone in the central nervous system and a peripheral chemosensory organ of Aplysia californica

Effects of steroid hormones on spermatogenesis and GnRH release in male Leopard frogs, Rana pipiens.

Disruption of pubertal onset by exogenous testosterone and estrogen in two species of rodents