NR4A Gene Expression Is Dynamically Regulated in the Ventral Tegmental Area Dopamine Neurons and Is Related to Expression of Dopamine Neurotransmission Genes
Open Access
- 20 September 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Molecular Neuroscience
- Vol. 46 (3), 545-553
- https://doi.org/10.1007/s12031-011-9642-z
Abstract
The NR4A transcription factors NR4A1, NR4A2, and NR4A3 (also known as Nur77, Nurr1, and Nor1, respectively) share similar DNA-binding properties and have been implicated in regulation of dopamine neurotransmission genes. Our current hypothesis is that NR4A gene expression is regulated by dopamine neuron activity and that induction of NR4A genes will increase expression of dopamine neurotransmission genes. Eticlopride and γ-butyrolactone (GBL) were used in wild-type (+/+) and Nurr1-null heterozygous (+/−) mice to determine the mechanism(s) regulating Nur77 and Nurr1 expression. Laser capture microdissection and real-time PCR was used to measure Nurr1 and Nur77 mRNA levels in the ventral tegmental area (VTA). Nur77 expression was significantly elevated 1 h after both GBL (twofold) and eticlopride (fourfold). In contrast, GBL significantly decreased Nurr1 expression in both genotypes, while eticlopride significantly increased Nurr1 expression only in the +/+ mice. In a separate group of mice, haloperidol injection significantly elevated Nur77 and Nor1, but not Nurr1 mRNA in the VTA within 1 h and significantly increased tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA expression by 4 h. These data demonstrate that the NR4A genes are dynamically regulated in dopamine neurons with maintenance of Nurr1 expression requiring dopamine neuron activity while both attenuation of dopamine autoreceptors activation and dopamine neuronal activity combining to induce Nur77 expression. Additionally, these data suggest that induction of NR4A genes could regulate TH and DAT expression and ultimately regulate dopamine neurotransmission.Keywords
This publication has 38 references indexed in Scilit:
- Nurr1 Is Required for Maintenance of Maturing and Adult Midbrain Dopamine NeuronsJournal of Neuroscience, 2009
- Alterations in amphetamine‐stimulated dopamine overflow due to the Nurr1‐null heterozygous genotype and postweaning isolationSynapse, 2008
- Regulation of GTP cyclohydrolase I expression by orphan receptor Nurr1 in cell culture andin vivoJournal of Neurochemistry, 2007
- The role of Nurr1 in the development of dopaminergic neurons and Parkinson's diseaseProgress in Neurobiology, 2005
- Induction Patterns of Transcription Factors of the Nur Family (Nurr1, Nur77, and Nor-1) by Typical and Atypical Antipsychotics in the Mouse Brain: Implication for Their Mechanism of ActionJournal of Pharmacology and Experimental Therapeutics, 2004
- Dimer-Specific Potentiation of NGFI-B (Nur77) Transcriptional Activity by the Protein Kinase A Pathway and AF-1-Dependent Coactivator RecruitmentMolecular and Cellular Biology, 2003
- Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activityBehavioural Brain Research, 2002
- Dopamine Biosynthesis Is Selectively Abolished in Substantia Nigra/Ventral Tegmental Area but Not in Hypothalamic Neurons in Mice with Targeted Disruption of the Nurr1 GeneMolecular and Cellular Neuroscience, 1998
- A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1.Genes & Development, 1995
- Identification of the DNA Binding Site for NGFI-B by Genetic Selection in YeastScience, 1991