The Kiss1 gene codes for kisspeptins, which have been implicated in the neuroendocrine regulation of reproduction. In the brain, Kiss1 mRNA-expressing neurons are located in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei. Kiss1 neurons in the AVPV appear to play a role in generating the preovulatory GnRH/LH surge, which occurs only in females and is organized perinatally by gonadal steroids. Because Kiss1 is involved in the sexually dimorphic GnRH/LH surge, we hypothesized that Kiss1 expression is sexually differentiated, with females having more Kiss1 neurons than either males or neonatally androgenized females. To test this, male and female rats were neonatally treated with androgen or vehicle; then, as adults, they were left intact or gonadectomized and implanted with capsules containing sex steroids or nothing. Kiss1 mRNA levels in the AVPV and ARC were determined by in situ hybridization. Normal females expressed significantly more Kiss1 mRNA in the AVPV than normal males, even under identical adult hormonal conditions. This Kiss1 sex difference was organized perinatally, as demonstrated by the observation that neonatally androgenized females displayed a male-like pattern of adulthood Kiss1 expression in the AVPV. In contrast, there was neither a sex difference nor an influence of neonatal treatment on Kiss1 expression in the ARC. Using double-labeling techniques, we determined that the sexually differentiated Kiss1 neurons in the AVPV are distinct from the sexually differentiated population of tyrosine hydroxylase (dopaminergic) neurons in this region. Our findings suggest that sex differences in kisspeptin signaling from the AVPV subserve the cellular mechanisms controlling the sexually differentiated GnRH/LH surge.

Kisspeptins are neuropeptides encoded by the Kiss1 gene, which have been implicated in the neuroendocrine regulation of gonadotropinreleasing hormone (GnRH) secretion. The goal of this study was to test the hypothesis that activation of Kiss1 neurons in the anteroventral periventricular nucleus (AVPV) is linked to the induction of the preovulatory luteinizing hormone (LH) surge in the rat. First, we determined that levels of Kiss1 mRNA in the AVPV peaked during the evening of proestrus, whereas Kiss1 mRNA in the arcuate nucleus (Arc) was at its nadir. Second, we corroborated this observation by demonstrating that Kiss1 mRNA is increased in the AVPV at the time of an estrogen (E)-and progesterone-induced LH surge in ovariectomized animals, whereas in the Arc, the expression of Kiss1 mRNA was decreased. Third, we found that most Kiss1 neurons in the AVPV coexpress the immediate early gene Fos coincidently with the LH surge, but virtually none coexpressed Fos on diestrus. In contrast, Kiss1 neurons in the Arc were Fos negative at the time of the LH surge as well as on diestrus. Finally, we found that most Kiss1 neurons in the AVPV and Arc express estrogen receptor ␣ mRNA, suggesting that E acts directly on these neurons. These results suggest that Kiss1 neurons in the AVPV play an active role in mediating the effects of E on the generation of the preovulatory GnRH/LH surge on proestrus.

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The G protein-coupled receptor Gpr54 and its ligand metastin (derived from the Kiss1 gene product kisspeptin) are key gatekeepers of sexual maturation. Gpr54 knockout mice demonstrate hypogonadotropic hypogonadism, but until recently, the phenotype of Kiss1 knockout mice was unknown. This report describes the reproductive phenotypes of mice carrying targeted deletions of Kiss1 or Gpr54 on the same genetic background. Both Kiss1 and Gpr54 knockout mice are viable but infertile and have abnormal sexual maturation; the majority of males lack preputial separation, and females have delayed vaginal opening and absence of estrous cycling. Kiss1 and Gpr54 knockout males have significantly smaller testes compared with controls. Gpr54 knockout females have smaller ovaries and uteri than wild-type females. However, Kiss1 knockout females demonstrate two distinct phenotypes: half have markedly reduced gonadal weights similar to those of Gpr54 knockout mice, whereas half exhibit persistent vaginal cornification and have gonadal weights comparable with those of wild-type females. FSH levels in both Kiss1 and Gpr54 knockout males and females are significantly lower than in controls. When injected with mouse metastin 43-52, a Gpr54 agonist, Gpr54 knockout mice fail to increase gonadotropins, whereas Kiss1 knockout mice respond with increased gonadotropin levels. In summary, both Kiss1 and Gpr54 knockout mice have abnormal sexual maturation consistent with hypogonadotropic hypogonadism, although Kiss1 knockout mice appear to be less severely affected than their receptor counterparts. Kiss1 knockout females demonstrate a bimodal phenotypic variability, with some animals having higher gonadal weight, larger vaginal opening, and persistent vaginal cornification.

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