Gottsch Michelle L, Navarro Víctor M, Zhao Zhen, Glidewell-Kenney Christine, Weiss Jeffrey, Jameson J Larry, Clifton Donald K, Levine Jon E, Steiner Robert A
Departments of Obstetrics and Gynecology, University of Washington, Seattle, Washington 98195, USA.
J Neurosci. 2009 Jul 22;29(29):9390-5. doi: 10.1523/JNEUROSCI.0763-09.2009.
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.
亲吻素是Kiss1基因的产物，在前脑表达。表达Kiss1的神经元在垂体促黄体生成素分泌和生殖调节中起关键作用。这些神经元是雌二醇-17β（E(2)）作用的直接靶点，E(2)通过雌激素受体α亚型（ERα）发挥作用来调节Kiss1的表达。在弓状核（Arc）中，强啡肽基因（Dyn）在Kiss1神经元中表达，E(2)抑制Kiss1 mRNA的表达。然而，E(2)诱导室旁核前腹侧部（AVPV）中Kiss1的表达。E(2)对Arc和AVPV中Kiss1的差异调节机制尚不清楚。ERα通过多种途径发出信号，可分为经典途径（涉及雌激素反应元件（ERE））或非经典途径（涉及不依赖ERE的机制）。为了阐明E(2)对Kiss1和Dyn表达作用的分子基础，我们研究了E(2)对ERα信号通路有靶向改变的小鼠大脑中Kiss1和Dyn mRNA的影响。我们发现，E(2)在AVPV中刺激Kiss1表达以及在Arc中抑制Dyn需要依赖ERE的途径，而E(2)在Arc中抑制Kiss1表达涉及不依赖ERE的机制。因此，不同的ERα信号通路可以在不同脑区差异调节相同基因的表达，并且E(2)可以通过不同的ERα信号通路在同一神经元内发挥作用来调节不同的神经递质基因。
