Differential regulation of dopaminergic gene expression by Er81.
Differential regulation of dopaminergic gene expression by Er81.
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DOI：
10.1523/jneurosci.0419-10.2010
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发表时间：
2010-03-31
期刊：
影响因子：
--
通讯作者：
Baker H
中科院分区：
文献类型：
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作者：
Cave JW;Akiba Y;Banerjee K;Bhosle S;Berlin R;Baker H
最近的一项研究提出，多巴胺能神经元的分化需要一个保守的“多巴胺基序”（DA基序），作为ETS DNA结合域转录因子的结合位点。在哺乳动物嗅球中，多巴胺能神经元分化所必需的一组五个基因（包括酪氨酸羟化酶，Th）的表达被认为是通过DA基序由ETS结构域转录因子ER 81调节的。为了研究ER 81的这种假定的调节作用，比较了这五个基因在单侧鼻孔闭合的成年野生型小鼠的嗅球和新生ER 81野生型和突变小鼠的嗅球中的表达水平。这些研究发现，ER 81仅对Th表达是必需的，而不是其他盒基因。ChIP和EMSA实验表明，ER 81直接结合到啮齿动物Th近端启动子中的共有结合位点/DA基序。然而，ER 81结合位点/DA-基序在Th近端启动子在其他哺乳动物中保守性较差。用犬OB组织进行的ChIP试验和用人Th近端启动子进行的EMSA试验均未检测到ER 81与这些物种的Th DA基序结合。这些结果表明，调节Th表达的直接结合的ER 81 Th启动子是一个物种特异性的机制。这些发现表明ER 81对于OB多巴胺能基因盒的表达不是必需的，并且DA基序不参与哺乳动物OB多巴胺能表型的分化。
A recent study proposed that differentiation of dopaminergic neurons requires a conserved “dopamine motif” (DA-motif) that functions as a binding site for ETS DNA binding domain transcription factors. In the mammalian olfactory bulb, the expression of a set of five genes (including tyrosine hydroxylase, Th) that are necessary for differentiation of dopaminergic neurons was suggested to be regulated by the ETS-domain transcription factor ER81 via the DA-motif. To investigate this putative regulatory role of ER81, expression levels of these five genes were compared both in olfactory bulbs of adult wild-type mice subjected to unilateral naris closure and in the olfactory bulbs of neonatal Er81 wild-type and mutant mice. These studies found that ER81 was necessary only for Th expression, and not the other cassette genes. ChIP and EMSA experiments showed that ER81 bound directly to a consensus binding site/DA-motif in the rodent Th proximal promoter. However, the ER81 binding site/DA-motif in the Th proximal promoter is poorly conserved in other mammals. Both ChIP assays with canine OB tissue and EMSA experiments with the human Th proximal promoter did not detect ER81 binding to the Th DA-motif from these species. These results suggest that regulation of Th expression by the direct binding of ER81 to the Th promoter is a species-specific mechanism. These findings indicate that ER81 is not necessary for expression of the OB dopaminergic gene cassette, and that the DA-motif is not involved in differentiation of the mammalian OB dopaminergic phenotype.