Regulation of Kiss1 and dynorphin gene expression in the murine brain by classical and nonclassical estrogen receptor pathways.
Regulation of Kiss1 and dynorphin gene expression in the murine brain by classical and nonclassical estrogen receptor pathways.
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DOI：
10.1523/jneurosci.0763-09.2009
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发表时间：
2009-07-22
期刊：
影响因子：
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通讯作者：
Steiner RA
中科院分区：
文献类型：
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作者：
Gottsch ML;Navarro VM;Zhao Z;Glidewell-Kenney C;Weiss J;Jameson JL;Clifton DK;Levine JE;Steiner RA
Kisspeptin是Kiss 1基因的产物，在前脑中表达。表达Kiss 1的神经元在调节垂体促黄体激素分泌和生殖中起着至关重要的作用。这些神经元是雌二醇-17 β（E2）作用的直接靶点，雌二醇-17 β（E2）通过雌激素受体α亚型（ERα）调节Kiss 1表达。在弓状核（Arc）中，强啡肽基因（Dyn）在Kiss 1神经元中表达，E2抑制Kiss 1 mRNA的表达。然而，E2诱导Kiss 1在前腹侧室周核（AVPV）的表达。E2对Arc和AVPV中Kiss 1的差异调节机制尚不清楚。ERα通过多种途径传递信号，可分为经典途径（涉及雌激素反应元件（ERE））和非经典途径（涉及不依赖于ERE的机制）。为了阐明E2对Kiss 1和Dyn表达作用的分子基础，我们研究了E2对ERα信号通路靶向改变小鼠脑中Kiss 1和Dyn mRNA的影响。我们发现，刺激Kiss 1表达的E2在AVPV和抑制Dyn在弧需要一个ERE依赖的途径，而抑制Kiss 1表达的E2在弧涉及ERE独立的机制。因此，不同的ERα信号通路可以在不同的大脑区域差异调节相同基因的表达，并且E2可以通过不同的ERα信号通路在同一神经元内作用以调节不同的神经递质基因。
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 through the estrogen receptor alpha 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 non-classical, 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 E2 in the AVPV and inhibition of Dyn in the Arc required an ERE-dependent pathway, whereas the inhibition of Kiss1 expression by E2 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.