Regulation of Kiss1 and dynorphin gene expression in the murine brain by classical and nonclassical estrogen receptor pathways

Abstract

Kisspeptin is a product of the Kiss1 gene and is expressed in the forebrain. Neurons that express Kiss1 play a crucial role in the regulation of pituitary luteinizing hormone secretion and reproduction. These neurons are the direct targets for the action of estradiol-17beta (E(2)), which acts via the estrogen receptor alpha isoform (ER alpha) to regulate Kiss1 expression. In the arcuate nucleus (Arc), where the dynorphin gene (Dyn) is expressed in Kiss1 neurons, E(2) inhibits the expression of Kiss1 mRNA. However, E(2) induces the expression of Kiss1 in the anteroventral periventricular nucleus (AVPV). The mechanism for differential regulation of Kiss1 in the Arc and AVPV by E(2) is unknown. ER alpha signals through multiple pathways, which can be categorized as either classical, involving the estrogen response element (ERE), or nonclassical, involving ERE-independent mechanisms. To elucidate the molecular basis for the action of E(2) on Kiss1 and Dyn expression, we studied the effects of E(2) on Kiss1 and Dyn mRNAs in the brains of mice bearing targeted alterations in the ER alpha signaling pathways. We found that stimulation of Kiss1 expression by E(2) in the AVPV and inhibition of Dyn in the Arc required an ERE-dependent pathway, whereas the inhibition of Kiss1 expression by E(2) in the Arc involved ERE-independent mechanisms. Thus, distinct ER alpha signaling pathways can differentially regulate the expression of identical genes across different brain regions, and E(2) can act within the same neuron through divergent ER alpha signaling pathways to regulate different neurotransmitter genes.

Figure 1.

The effects of estradiol on the relative number of cells expressing Kiss1 mRNA in the AVPV of female ERα^+/+, ERα^−/−, or ERα^AA/− mice. There were 5–6 animals per group; bars represent means + SEM.

Figure 2.

Photomicrographs depicting the effects of estradiol on Kiss1 mRNA expression in the AVPV of female ERα^+/+ and ERα^AA/− mice. Silver grains (white dots) represent Kiss1 mRNA. Photomicrographs depicting Kiss1 mRNA expression in ERα^−/− mice were omitted, as they were the same as ERα^AA/− mice. 3V, Third ventricle. Scale bars, 100 μm.

Figure 3.

The effects of estradiol on the relative number of cells expressing Kiss1 mRNA in the Arc of female ERα^+/+, ERα^−/−, or ERα^AA/− mice. There were 5–6 animals per group; bars represent means + SEM.

Figure 4.

Photomicrographs depicting the effects of estradiol on Kiss1 mRNA expression in the Arc of female ERα^+/+, ERα^−/−, and ERα^AA/− mice. Silver grains (white dots) represent Kiss1 mRNA. 3V, Third ventricle. Scale bars, 100 μm.

Figure 5.

The effects of estradiol on the relative number of cells expressing Dyn mRNA in the Arc of female ERα^+/+ and ERα^AA/− mice. There were 5–6 animals per group; bars represent means + SEM.

Figure 6.

Photomicrographs depicting the effects of estradiol on Dyn mRNA expression in the Arc of female ERα^+/+ and ERα^AA/− mice. Silver grains (white dots) represent Dyn mRNA. 3V, Third ventricle. Scale bar, 50 μm.