VIP is a transcriptional target of Nurr1 in dopaminergic cells
VIP is a transcriptional target of Nurr1 in dopaminergic cells
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DOI：
10.1016/j.expneurol.2006.08.005
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发表时间：
2007-01-01
影响因子：
5.3
通讯作者：
Federoff, Howard J.
中科院分区：
文献类型：
--
作者：
Luo, Yu;Henricksen, Leigh A.;Federoff, Howard J.
孤儿核受体Nurr 1是腹侧中脑多巴胺能神经元发育所必需的。这些神经元在帕金森病患者中总是丢失。Nurr 1 mRNA的表达并不局限于发育中的中脑，但Nurr 1似乎是必不可少的成熟的祖细胞完全有丝分裂后多巴胺能神经元和/或一旦形成，他们的生存。Nurr 1在对神经元发育和/或维持重要的基因的反式激活中的功能尚不清楚。为了表征Nurr 1的潜在下游靶基因，我们试图鉴定受Nurr 1表达差异影响的mRNA。使用多巴胺能细胞系，其中Nurr 1含量受到严格调控，差异显示分析确定转录改变Nurr 1的表达，包括编码血管活性肠肽（VIP）的mRNA。在这里，我们证明，Nurr 1调节VIP的mRNA和蛋白质水平，并通过Nurr 1响应顺式元件反式激活VIP启动子。此外，多巴胺能细胞释放和利用VIP来介导百草枯攻击时的生存。Nurr 1对VIP的调节也在体内得到证实，因为Nurr 1功能的丧失会导致发育中的中脑内VIP mRNA水平下降。(c)2006年爱思唯尔公司All rights reserved.
The orphan nuclear receptor Nurr1 is required for the development of the ventral mesencephalic dopaminergic neurons. These are the same neurons that are invariantly lost in patients with Parkinson's disease. Nurr1 mRNA expression is not confined to the developing midbrain, and yet Nurr1 appears to be essential for either the maturation of progenitors into fully post-mitotic dopaminergic neurons and/or once formed, their survival. The function of Nurr1 in the transactivation of gene(s) important for neuronal development and/or maintenance is uncharacterized. To characterize potential downstream target genes of Nurr1, we sought to identify mRNAs that are differentially affected by Nurr1 expression. Using a dopaminergic cell line in which Nurr1 content was tightly regulated, differential display analysis identified transcripts altered by Nurr1 expression, including the mRNA encoding vasoactive intestinal peptide (VIP). Herein, we demonstrate that Nurr1 regulates VIP mRNA and protein levels, and transactivates the VIP promoter through Nurr1-responsive cis elements. In addition, dopaminergic cells release and utilize VIP to mediate survival when challenged with paraquat. Nurr1 regulation of VIP is also demonstrated in vivo as loss of Nurr1 function results in diminished VIP mRNA levels within the developing midbrain. (c) 2006 Elsevier Inc. All rights reserved.