VIP is a transcriptional target of Nurr1 in dopaminergic cells.
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.
Luo
Yu
Y
Dept. of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA.
Henricksen
Leigh A
LA
Giuliano
Rita E
RE
Prifti
Llanda
L
Callahan
Linda M
LM
Federoff
Howard J
HJ
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006540:Herbicides / Q000633:toxicity; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010269:Paraquat / Q000633:toxicity; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D013378:Substantia Nigra / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D014660:Vasoactive Intestinal Peptide / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D006540:Herbicides; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; D014157:Transcription Factors; D014660:Vasoactive Intestinal Peptide; D010269:Paraquat; D004298:Dopamine