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

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-17β(E₂ ), which acts via the estrogen receptor α isoform (ERα) to regulate Kiss1 expression. In the arcuate nucleus (Arc), where the dynorphin gene (Dyn) is expressed in Kiss1 neurons, E₂ inhibits the expression of Kiss1 mRNA. However, E₂ induces the expression of Kiss1 in the anteroventral periventricular nucleus (AVPV). The mechanism for differential regulation of Kiss1 in the Arc and AVPV by E₂ is unknown. ERα 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 E₂ on Kiss1 and Dyn expression, we studied the effects of E₂ on Kiss1 and Dyn mRNAs in the brains of mice bearing targeted alterations in the ERα 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 ERα signaling pathways can differentially regulate the expression of identical genes across different brain regions, and E₂ can act within the same neuron through divergent ERα signaling pathways to regulate different neurotransmitter genes.