Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease
Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease
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DOI：
10.1016/j.nbd.2008.05.005
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发表时间：
2008-09-01
影响因子：
6.1
通讯作者：
Thomas, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Desplats, Paula A.;Lambert, James R.;Thomas, Elizabeth A.
转录失调已成为亨廷顿病（HD）的主要致病机制，其主要与纹状体中的神经病理学变化相关。在这里，我们证明了Bcl 11b（a.k.a. CTIP 2），一种在成年纹状体中表现出高度富集定位的转录因子，在HD细胞、小鼠模型和人类受试者中显著降低，并且Bcl 11b的过表达减弱了突变型亨廷顿蛋白在培养的纹状体神经元中的毒性作用。我们发现，Bcl 11 b直接激活纹状体富集基因的近端启动子区域，并可以增加纹状体表达基因的mRNA水平。我们进一步证明了Bcl 11b和亨廷顿蛋白在培养的细胞和脑匀浆从HD R6/1和YAC 72转基因小鼠之间的相互作用。我们建议，隔离和/或Bcl 11b在HD中的表达减少是负责的，至少部分，纹状体基因表达失调观察HD，并可能有助于在这种疾病中观察到的病理学的特异性。(C)2008年爱思唯尔公司All rights reserved.
Transcriptional dysregulation has emerged as a central pathogenic mechanism in Huntington's disease (HD), which is associated with neuropathological changes predominantly in the striatum. Here we demonstrate that expression of Bcl11b (a.k.a. CTIP2), a transcription factor exhibiting highly-enriched localization in adult striatum, is significantly decreased in HD cells, mouse models and human subjects and that overexpression of Bcl11b attenuates toxic effects of mutant huntingtin in cultured striatal neurons. We show that Bcl11b directly activates the proximal promoter regions of striatal-enriched genes and can increase mRNA levels of striatal-expressing genes. We further demonstrate an interaction between Bcl11b and huntingtin protein in cultured cells and brain homogenates from HD R6/1 and YAC72 transgenic mice. We propose that sequestration and/or decreased expression of Bcl11b in HD is responsible, at least in part, for the dysregulation of striatal gene expression observed in HD and may contribute to the specificity of pathology observed in this disease. (C) 2008 Elsevier Inc. All rights reserved.