The role of kisspeptin and neurotensin signaling in the central regulation of gonadotropin secretion.

摘要

In mammals, reproduction is controlled by a network of neurons in the basal forebrain that secrete gonadotropin-releasing hormone (GnRH); however, the mechanisms that control the secretion of GnRH are not fully understood. The objective of this research was to elucidate the function of two neuropeptides---kisspeptin and neurotensin---in the regulation of GnRH secretion. The Kiss1 gene codes for kisspeptin, which directly stimulates GnRH secretion. To test the hypothesis that kisspeptin mediates the steroid-dependent, negative feedback control of GnRH secretion, I examined the effect of testosterone on Kiss1 gene expression in the brain of the male mouse. I found that testosterone inhibits the expression of Kiss1 mRNA in the arcuate nucleus, where negative feedback is coordinated, suggesting that Kiss1 neurons in this region transduce the action of sex steroids and thereby govern GnRH secretion. Kiss1 neurons are also found in abundance in the anteroventral periventricular nucleus (AVPV) in the hypothalamus, which is a critical site of the action of estradiol for generating the preovulatory surge of GnRH and luteinizing hormone (LH) in the female. To test the hypothesis that kisspeptin signaling is an essential element for producing the GnRH/LH surge, I examined whether estradiol could evoke a GnRH/LH surge in mice bearing a disabling mutation of the kisspeptin receptor gene (Kiss1r KO). I observed that estradiol could elicit a GnRH/LH surge in both wildtype and Kiss1r KOs. These findings suggest that kisspeptin/Kiss1r signaling is not essential for generating the estradiol-induced GnRH/LH surge. Next, I postulated that neurotensin---a product of the Nts gene---could serve as an alternate signal to generate the surge. I found that estradiol induced the expression of Nts mRNA in the AVPV and that the expression of Nts mRNA is increased at the time of the estradiol-induced LH surge in the medial preoptic nucleus of both Kiss1r KO and wildtype mice. Nevertheless, injection of neurotensin into the brain had no effect on LH secretion. These observations indicate that Nts is a target for the action of estradiol, but neurotensin does not appear to stimulate GnRH/LH secretion in the mouse.