The function and mechanisms of Nurr1 action in midbrain dopaminergic neurons, from development and maintenance to survival

Abstract

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.