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

TLDR

Kisspeptins, encoded by the Kiss1 gene, bind the GPR54 receptor and are implicated in the neuroendocrine regulation of GnRH secretion. The study tests whether testosterone regulates Kiss1 gene expression. Expression of KiSS‑1 mRNA was compared among intact, castrated, and castrated/testosterone‑treated male mice. Castration increased KiSS‑1 mRNA in the arcuate nucleus and decreased it in the anteroventral periventricular nucleus, with testosterone reversing the Arc effect and stimulating the AVPV effect; these actions were mediated by both estrogen and androgen receptors, as shown by estrogen mimicking the Arc response, partial dihydrotestosterone mimicry, and loss of effect in ERα or AR mutant mice, indicating that Arc KiSS‑1 neurons are targets of testosterone’s negative feedback on GnRH secretion while AVPV KiSS‑1 neurons mediate testosterone‑dependent processes.

Abstract

Kisspeptins are products of the Kiss1 gene, which bind to GPR54, a G protein-coupled receptor. Kisspeptins and GPR54 have been implicated in the neuroendocrine regulation of GnRH secretion. To test the hypothesis that testosterone regulates Kiss1 gene expression, we compared the expression of KiSS-1 mRNA among groups of intact, castrated, and castrated/testosterone (T)-treated male mice. In the arcuate nucleus (Arc), castration resulted in a significant increase in KiSS-1 mRNA, which was completely reversed with T replacement, whereas in the anteroventral periventricular nucleus, the results were the opposite, i.e. castration decreased and T increased KiSS-1 mRNA expression. In the Arc, the effects of T on KiSS-1 mRNA were completely mimicked by estrogen but only partially mimicked by dihydrotestosterone, a nonaromatizable 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 ERalpha or a hypomorphic allele to the AR revealed that the effects of T are mediated by both ERalpha and AR pathways, which was confirmed by the presence of either ERalpha 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 by T, are targets for the negative feedback regulation of GnRH secretion, whereas KiSS-1 neurons in the anteroventral periventricular nucleus, whose activity is stimulated by T, may mediate other T-dependent processes.