Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1
Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1
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DOI：
10.1093/hmg/ddm162
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发表时间：
2007-09-01
影响因子：
3.5
通讯作者：
Matilla-Duenas, Antoni
中科院分区：
文献类型：
--
作者：
Goold, Robert;Hubank, Michael;Matilla-Duenas, Antoni
Aaxin 1(Atxn1)是一种功能未知的蛋白，与脊髓小脑性共济失调1型(SCA1)相关，SCA1是一种起病晚的神经退行性疾病，伴有不同程度的小脑性共济失调、眼肌麻痹和神经病。SCA1是由Atxn1内的一种膨胀的聚谷氨酰胺(PolyQ)引发的毒性作用引起的，导致小脑、脑干和脊髓小脑束的神经退化。为了深入了解Atxn1的功能，我们通过微阵列分析了Atxn1基因缺失小鼠的小脑基因表达谱，并确定了受Sp1依赖的转录调控的基因表达的变化，包括多巴胺受体D2(Drd2)、维甲酸/甲状腺激素和Wnt信号转导。有趣的是，在小脑Purkinje细胞中，表达致病的人类Atxn1的转基因小鼠和Atxn1缺失的转基因小鼠的Drd2表达水平都降低了。我们在人神经母细胞瘤SH-SY5Y细胞中的共转染实验和荧光素酶检测为Atxn1及其AXH模块对Drd2的转录调控提供了证据。我们发现Atxn1在体内位于Drd2启动子上，并与锌指转录因子Sp1相互作用并协同作用，共同调节Drd2的表达。相互作用和转录效应是由Atxn1内的AXH结构域介导的，并被Atxn1内的扩展多聚Q所取消。因此，本研究发现了受Atxn1调控的可能导致SCA1运动缺陷的新的分子靶点，并为Atxn1共同调控转录的机制提供了新的见解。
Ataxin 1 (Atxn1) is a protein of unknown function associated with spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease of late onset with variable degrees of cerebellar ataxia, ophthalmoplegia and neuropathy. SCA1 is caused by the toxic effects triggered by an expanded polyglutamine (polyQ) within Atxn1 resulting in neurodegeneration in the cerebellum, brain stem and spinocerebellar tracts. To gain insights into Atxn1 function, we have analysed the cerebellar gene expression profiles by microarray analysis in Atxn1-null mice, and identified alterations in expression of genes regulated by Sp1-dependent transcription, including the dopamine receptor D2 (Drd2), retinoic acid/thyroid hormone and Wnt-signalling. Interestingly, Drd2 expression levels are reduced in both Atxn1-null and transgenic mice expressing a pathogenic human Atxn1 with an expanded polyglutamine in cerebellar Purkinje cells. Our co-transfection experiments in human neuroblastoma SH-SY5Y cells and luciferase assays provide evidence for transcriptional regulation of Drd2 by Atxn1 and its AXH module. We show that Atxn1 occupies at the Drd2 promoter in vivo, and interacts and functions synergistically with the zinc-finger transcription factor Sp1 to co-regulate Drd2 expression. The interaction and transcriptional effects are mediated by the AXH domain within Atxn1 and are abrogated by the expanded polyQ within Atxn1. Therefore, this study identifies novel molecular targets that are regulated by Atxn1 which might contribute to the motor deficits in SCA1, and provides new insights into the mechanisms by which Atxn1 co-regulates transcription.