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-17 beta(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.