Jacobsen Kirsten X, Vanderluit Jacqueline L, Slack Ruth S, Albert Paul R
Ottawa Health Research Institute (Neuroscience) and Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON Canada.
Mol Cell Neurosci. 2008 Jul;38(3):349-58. doi: 10.1016/j.mcn.2008.03.007. Epub 2008 Apr 1.
Mammalian HES1 and HES5 are abundant in developing CNS and inhibit neurogenesis, while HES6 promotes neurogenesis. An early serotonergic differentiation marker, the 5-HT1A receptor, is repressed by HES5 and DEAF1 which recognize the C(-1019), but not G(-1019) allele of a human 5-HT1A promoter polymorphism associated with mood disorders. We tested whether HES1 and HES6 regulate transcriptional activity at this element. HES1 strongly repressed 5-HT1A transcription in neuronal and non-neuronal cells, while HES6 reversed HES1- and HES5-mediated repression. Mutation of a putative HES consensus site blocked HES1 and HES5, but, unlike HES5, HES1 repressed at the G(-1019) allele. To address its role in vivo, the temporal expression of 5-HT1A receptor RNA and protein was examined in HES1-/- mice, and elevated levels in E12.5 hindbrain and midbrain were observed. Thus, HES1 and HES6 oppositely regulate 5-HT1A receptor transcription and HES1 is required for its correct developmental expression.
哺乳动物的HES1和HES5在发育中的中枢神经系统中含量丰富，并抑制神经发生，而HES6则促进神经发生。一种早期的血清素能分化标志物，即5-HT1A受体，受到HES5和DEAF1的抑制，它们识别与情绪障碍相关的人类5-HT1A启动子多态性的C(-1019)等位基因，而非G(-1019)等位基因。我们测试了HES1和HES6是否调节该元件的转录活性。HES1在神经元和非神经元细胞中强烈抑制5-HT1A转录，而HES6则逆转HES1和HES5介导的抑制作用。一个假定的HES共有位点的突变阻断了HES1和HES5，但与HES5不同的是，HES1在G(-1019)等位基因处起抑制作用。为了研究其在体内的作用，我们检测了HES1基因敲除小鼠中5-HT1A受体RNA和蛋白质的时间表达，发现在E12.5期的后脑和中脑中其水平升高。因此，HES1和HES6对5-HT1A受体转录的调节作用相反，且HES1是其正确发育表达所必需的。
