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...

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Bibliographic Details
Published in:Experimental neurology 2007, Vol.203 (1), p.221-232
Main Authors: Luo, Yu, Henricksen, Leigh A., Giuliano, Rita E., Prifti, Llanda, Callahan, Linda M., Federoff, Howard J.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Line, Tumor
Cell Survival - drug effects
Cell Survival - genetics
Development. Senescence. Regeneration. Transplantation
Differential display
DNA-Binding Proteins - genetics
Dopamine - metabolism
Dopaminergic neuron
Down-Regulation - drug effects
Down-Regulation - genetics
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation, Developmental - genetics
Herbicides - toxicity
In situ hybridization
Medical sciences
Mesencephalon - cytology
Mesencephalon - embryology
Mesencephalon - metabolism
Mice
Mice, Knockout
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Neurosurgery
Nuclear Receptor Subfamily 4, Group A, Member 2
Nurr1
Paraquat - toxicity
Parkinson Disease - genetics
Parkinson Disease - metabolism
Parkinson Disease - physiopathology
Parkinson's disease
Promoter Regions, Genetic - genetics
Regulatory Elements, Transcriptional - genetics
RNA, Messenger - metabolism
Skull, brain, vascular surgery
Substantia Nigra - cytology
Substantia Nigra - embryology
Substantia Nigra - metabolism
Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases
Transcription Factors - genetics
Transcriptional Activation - genetics
Vasoactive intestinal peptide
Vasoactive Intestinal Peptide - genetics
Vasoactive Intestinal Peptide - metabolism
Vertebrates: nervous system and sense organs
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Summary: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.
ISSN:0014-4886
1090-2430
DOI:10.1016/j.expneurol.2006.08.005