Department of Neurological Surgery, Case Western Reserve University, School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA.
Int Rev Neurobiol. 2012;102:1-22. doi: 10.1016/B978-0-12-386986-9.00001-6.
Nurr1 is critical for the development and maintenance of midbrain dopaminergic (DA) neurons in mouse. Loss of Nurr1 function early during development in mice leads to the absence of midbrain DA neurons. Reduction of Nurr1 function in adulthood leads to a slowly progressive loss of striatal DA and markers for DAergic neurons, supporting its selective roles in the maintenance of DAergic neuronal survival and function. To understand the molecular mechanisms of Nurr1 action, our group has identified VIP as a potential target gene of Nurr1. Nurr1 regulates VIP mRNA and protein levels, and transactivates the VIP promoter through Nurr1-responsive cis elements. Nurr1 loss of function leads to the decrease of VIP mRNA level in developing midbrain, suggesting that Nurr1 is involved in the in vivo regulation of VIP expression in midbrain. Our group has also cloned a novel protein interactor for Nurr1. We identified a family of gene products that interact and regulate the activity of Nurr1 by screening yeast two-hybrid library and termed the longest splicing form, NuIP. In vivo NuIP protein is largely colocalized with Nurr1 in adult midbrain dopaminergic neurons. NuIP interacts and positively regulates the activity of Nurr1 protein and could also possibly mediate cross talk between Nurr1 and GTPase mediated signaling pathways. Other recently identified potential target genes and interacting proteins of Nurr1 are also summarized and discussed in this review.
Nurr1 对于小鼠中脑多巴胺能（DA）神经元的发育和维持至关重要。在小鼠发育早期丧失 Nurr1 功能会导致中脑 DA 神经元缺失。成年后 Nurr1 功能的降低会导致纹状体 DA 及其 DA 能神经元标志物的缓慢进行性丧失，支持其在维持 DA 能神经元存活和功能方面的选择性作用。为了了解 Nurr1 作用的分子机制，我们的研究小组已经确定 VIP 是 Nurr1 的一个潜在靶基因。Nurr1 调节 VIP mRNA 和蛋白水平，并通过 Nurr1 反应性顺式元件转录激活 VIP 启动子。Nurr1 功能丧失会导致发育中脑 VIP mRNA 水平降低，这表明 Nurr1 参与了中脑 VIP 表达的体内调节。我们的研究小组还克隆了 Nurr1 的一种新型蛋白相互作用因子。通过筛选酵母双杂交文库，我们鉴定了一组相互作用并调节 Nurr1 活性的基因产物，并将最长的剪接形式命名为 NuIP。体内 NuIP 蛋白在成年中脑多巴胺能神经元中与 Nurr1 大量共定位。NuIP 与 Nurr1 蛋白相互作用并正向调节其活性，并且还可能介导 Nurr1 与 GTPase 介导的信号通路之间的串扰。本综述还总结和讨论了最近鉴定的 Nurr1 的其他潜在靶基因和相互作用蛋白。
