Luo Yu, Henricksen Leigh A, Giuliano Rita E, Prifti Llanda, Callahan Linda M, Federoff Howard J
Dept. of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA.
Exp Neurol. 2007 Jan;203(1):221-32. doi: 10.1016/j.expneurol.2006.08.005. Epub 2006 Sep 26.
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.
孤儿核受体Nurr1是腹侧中脑多巴胺能神经元发育所必需的。这些神经元正是帕金森病患者中始终会缺失的神经元。Nurr1 mRNA的表达并不局限于发育中的中脑，然而，Nurr1对于祖细胞成熟为完全停止有丝分裂的多巴胺能神经元和/或一旦形成后的存活似乎至关重要。Nurr1在对神经元发育和/或维持重要的基因反式激活中的功能尚未明确。为了鉴定Nurr1潜在的下游靶基因，我们试图识别受Nurr1表达差异影响的mRNA。利用一种Nurr1含量受到严格调控的多巴胺能细胞系，差异显示分析鉴定出了受Nurr1表达改变的转录本，包括编码血管活性肠肽（VIP）的mRNA。在此，我们证明Nurr1调节VIP mRNA和蛋白水平，并通过Nurr1反应性顺式元件反式激活VIP启动子。此外，当受到百草枯攻击时，多巴胺能细胞释放并利用VIP来介导存活。Nurr1对VIP的调节在体内也得到了证实，因为Nurr1功能丧失导致发育中的中脑内VIP mRNA水平降低。
