Czesak Margaret, Lemonde Sylvie, Peterson Erica A, Rogaeva Anastasia, Albert Paul R
Ottawa Health Research Institute (Neuroscience), Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1H 8M5, Canada.
J Neurosci. 2006 Feb 8;26(6):1864-71. doi: 10.1523/JNEUROSCI.2643-05.2006.
The serotonin-1A (5-HT1A) receptor is the primary somatodendritic autoreceptor that inhibits the activity of serotonergic raphe neurons and is also expressed in nonserotonergic cortical and limbic neurons. Alterations in 5-HT1A receptor levels are implicated in mood disorders, and a functional C(-1019)G 5-HT1A promoter polymorphism has been associated with depression, suicide, and panic disorder. We examined the cell-specific activity of identified transcription factors, human nuclear deformed epidermal autoregulatory factor-1 (DEAF-1)-related (NUDR)/Deaf-1 and Hes5, at the 5-HT1A C(-1019) site. In serotonergic raphe RN46A cells, Deaf-1 and Hes5 repressed the 5-HT1A receptor gene at the C(-1019)-allele but not the G(-1019)-allele. However, in nonserotonergic cells that express 5-HT1A receptors (septal SN48, neuroblastoma SKN-SH, and neuroblastoma/glioma NG108-15 cells), Deaf-1 enhanced 5-HT1A promoter activity at the C(-1019)-allele but not the G-allele, whereas Hes5 repressed in all cell types. The enhancer activity of Deaf-1 was orientation independent and competed out Hes5 repression. To test whether Deaf-1 activity is intrinsic, the activity of a Gal4DBD (DNA binding domain)-Deaf-1 fusion protein at a heterologous Gal4 DNA element was examined. Gal4DBD-Deaf-1 repressed transcription in RN46A cells but enhanced transcription in SN48 cells, indicating that these opposite activities are intrinsic to Deaf-1. Repressor or enhancer activities of Deaf-1 or Gal4DBD-Deaf-1 were blocked by histone deacetylase inhibitor trichostatin A. Thus, the intrinsic activity of Deaf-1 at the 5-HT1A promoter is opposite in presynaptic versus postsynaptic neuronal cells and requires deacetylation. Cell-specific regulation by Deaf-1 could underlie region-specific alterations in 5-HT1A receptor expression in different mood disorders.
5-羟色胺1A（5-HT1A）受体是主要的胞体树突自身受体，可抑制5-羟色胺能中缝神经元的活性，且在非5-羟色胺能的皮质和边缘神经元中也有表达。5-HT1A受体水平的改变与情绪障碍有关，功能性C（-1019）G 5-HT1A启动子多态性与抑郁症、自杀及惊恐障碍相关。我们检测了已鉴定的转录因子，即人类核变形表皮自身调节因子-1（DEAF-1）相关（NUDR）/Deaf-1和Hes5，在5-HT1A C（-1019）位点的细胞特异性活性。在5-羟色胺能中缝RN46A细胞中，Deaf-1和Hes5抑制C（-1019）等位基因的5-HT1A受体基因，但不抑制G（-1019）等位基因。然而，在表达5-HT1A受体的非5-羟色胺能细胞（隔区SN48、神经母细胞瘤SKN-SH和神经母细胞瘤/胶质瘤NG108-15细胞）中，Deaf-1增强C（-1019）等位基因的5-HT1A启动子活性，但不增强G等位基因的活性，而Hes5在所有细胞类型中均起抑制作用。Deaf-1的增强子活性不依赖于方向，并能竞争消除Hes5的抑制作用。为了检测Deaf-1的活性是否为内在特性，我们检测了Gal4DBD（DNA结合结构域）-Deaf-1融合蛋白在异源Gal4 DNA元件处的活性。Gal4DBD-Deaf-1在RN46A细胞中抑制转录，但在SN48细胞中增强转录，这表明这些相反的活性是Deaf-1所固有的。Deaf-1或Gal4DBD-Deaf-1的阻遏或增强子活性被组蛋白脱乙酰酶抑制剂曲古抑菌素A阻断。因此，Deaf-1在5-HT1A启动子处的内在活性在突触前与突触后神经元细胞中相反，且需要去乙酰化。Deaf-1的细胞特异性调节可能是不同情绪障碍中5-HT1A受体表达区域特异性改变的基础。
