Nuclear receptor 4A2

The nuclear receptor 4A2 (NR4A2) (nuclear receptor subfamily 4 group A member 2) also known as nuclear receptor related 1 protein (NURR1) is a protein that in humans is encoded by the NR4A2 gene. NR4A2 is a member of the nuclear receptor family of intracellular transcription factors.

NR4A2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1OVL
Identifiers
Aliases	NR4A2, HZF-3, NOT, NURR1, RNR1, TINUR, nuclear receptor subfamily 4 group A member 2
External IDs	OMIM: 601828; MGI: 1352456; HomoloGene: 4509; GeneCards: NR4A2; OMA:NR4A2 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 2q24.1 Start 156,324,437 bp End 156,342,348 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2 C1.1|2 31.66 cM Start 56,996,842 bp End 57,014,015 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of paranasal sinus gastric mucosa trachea spinal ganglia cartilage tissue mucosa of urinary bladder cardia seminal vesicula trigeminal ganglion tail of epididymis Top expressed in habenula ventral tegmental area parotid gland Region I of hippocampus proper substantia nigra lobe of cerebellum cerebellar vermis subiculum epithelium of stomach submandibular gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function retinoid X receptor binding protein homodimerization activity sequence-specific DNA binding beta-catenin binding DNA-binding transcription activator activity, RNA polymerase II-specific steroid hormone receptor activity RNA polymerase II transcription regulatory region sequence-specific DNA binding protein binding glucocorticoid receptor binding DNA-binding transcription factor activity zinc ion binding metal ion binding DNA binding protein heterodimerization activity nuclear receptor activity RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component cytoplasm nucleus nucleoplasm nuclear speck transcription regulator complex Biological process dopaminergic neuron differentiation cellular response to oxidative stress response to hypoxia response to amphetamine nervous system development neuron maturation steroid hormone mediated signaling pathway central nervous system projection neuron axonogenesis regulation of transcription, DNA-templated central nervous system neuron differentiation negative regulation of apoptotic signaling pathway cellular response to corticotropin-releasing hormone stimulus positive regulation of transcription, DNA-templated regulation of respiratory gaseous exchange regulation of dopamine metabolic process adult locomotory behavior regulation of gene expression habenula development positive regulation of catalytic activity fat cell differentiation post-embryonic development dopamine biosynthetic process transcription initiation from RNA polymerase II promoter negative regulation of neuron apoptotic process canonical Wnt signaling pathway general adaptation syndrome neuron differentiation signal transduction dopamine metabolic process transcription, DNA-templated intracellular receptor signaling pathway neuron migration negative regulation of transcription by RNA polymerase II positive regulation of transcription by RNA polymerase II cellular response to extracellular stimulus midbrain dopaminergic neuron differentiation gene expression transcription by RNA polymerase II Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4929 18227 Ensembl ENSG00000153234 ENSMUSG00000026826 UniProt P43354 Q06219 RefSeq (mRNA) NM_006186 NM_173171 NM_173172 NM_173173 NM_001139509 NM_013613 RefSeq (protein) NP_006177 NP_775265 NP_006177.1 NP_001132981 NP_038641 Location (UCSC) Chr 2: 156.32 – 156.34 Mb Chr 2: 57 – 57.01 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

NR4A2 plays a key role in the maintenance of the dopaminergic system of the brain. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson's disease and schizophrenia. Misregulation of this gene may be associated with rheumatoid arthritis. Four transcript variants encoding four distinct isoforms have been identified for this gene. Additional alternate splice variants may exist, but their full-length nature has not been determined.

This protein is thought to be critical to development of the dopaminergic phenotype in the midbrain, as mice without NR4A2 are lacking expression of this phenotype. This is further confirmed by studies showing that forced NR4A2 expression in naïve precursor cells leads to complete dopaminergic phenotype gene expression.

While NR4A2 is a key protein in inducing this phenotype, there are other factors required, as expressing NR4A2 in isolation fails to produce it. One of these suggested factors is winged-helix transcription factor 2 (Foxa2). Studies have found these two factors to be within the same region of developing dopaminergic neurons, and both were required to have expression for the dopaminergic phenotype.

Structure

One investigation conducted research on the structure and found that NR4A2 does not contain a ligand-binding cavity but a patch filled with hydrophobic side chains. Non-polar amino acid residues of NR4A2’s co-regulators, SMRT and NCoR, bind to this hydrophobic patch. Analysis of tertiary structure has shown that the binding surface of the ligand-binding domain is located on the grooves of the 11th and 12th alpha helices. This study also found essential structural components of this hydrophobic patch, to be the three amino acids residues, F574, F592, L593; mutation of any these three inhibits LBD activity.

Clinical significance

Role in disease

Mutations in NR4A2 have been associated with various disorders, including Parkinson's disease, schizophrenia, manic depression, and autism. De novo gene deletions that affect NR4A2 have been identified in some individuals with intellectual disability and language impairment, some of whom meet DSM-5 criteria for an autism diagnosis.

Inflammation

Research has been conducted on NR4A2’s role in inflammation, and may provide important information in treating disorders caused by dopaminergic neuron disease. Inflammation in the central nervous system can result from activated microglia (macrophage analogs for the central nervous system) and other pro-inflammatory factors, such as bacterial lipopolysaccharide (LPS). LPS binds to toll-like receptors (TLR), which induces inflammatory gene expression by promoting signal-dependent transcription factors. To determine which cells are dopaminergic, experiments measured the enzyme tyrosine hydroxylase (TH), which is needed for dopamine synthesis. It has been shown that NR4A2 protects dopaminergic neurons from LPS-induced inflammation by reducing inflammatory gene expression in microglia and astrocytes. When a short hairpin RNA for NR4A2 was expressed in microglia and astrocytes, these cells produced inflammatory mediators such as TNF-alpha, nitric oxide synthase, and interleukin-1 beta (IL-1β), supporting the conclusion that reduced NR4A2 promotes inflammation and leads to cell death of dopaminergic neurons. NR4A2 interacts with the transcription factor complex NF-κB-p65 on the inflammatory gene promoters. However, NR4A2 is dependent on other factors to be able to participate in these interactions. NR4A2 needs to be sumoylated and its co-regulating factor, glycogen synthase kinase 3, needs to be phosphorylated for these interactions to occur. Sumolyated NR4A2 recruits CoREST, a complex made of several proteins that assembles chromatin remodeling enzymes. The NR4A2/CoREST complex inhibits transcription of inflammatory genes.

Applications

NR4A2 induces tyrosine hydroxylase (TH) expression, which eventually leads to differentiation into dopaminergic neurons. NR4A2 has been demonstrated to induce differentiation in CNS precursor cells in vitro but they require additional factors to reach full maturity and dopaminergic differentiation. Therefore, NR4A2 modulation may be promising for generation of dopaminergic neurons for Parkinson's disease research, yet implantation of these induced cells as therapy treatments, has had limited results.

NR4A2 mRNA may be a useful biomarker for Parkinson's disease in combination with inflammatory cytokines.

Knockout studies

Studies have shown that heterozygous knockout mice for the NR4A2 gene demonstrate reduced dopamine release. Initially this was compensated for by a decrease in the rate of dopamine reuptake; however, over time this reuptake could not make up for the reduced amount of dopamine being released. Coupled with the loss of dopamine receptor neurons, this can result in the onset of symptoms for Parkinson's disease.

Interactions

NR4A2 has been shown to interact with:

• Beta-catenin,
• Pituitary homeobox 3,
• Retinoic acid receptor alpha, and
• Retinoic acid receptor beta.

Further reading

• Le W, Appel SH (February 2004). "Mutant genes responsible for Parkinson's disease". Current Opinion in Pharmacology. 4 (1): 79–84. doi:10.1016/j.coph.2003.09.005. PMID 15018843.
• Wedler B, Wüstenberg PW, Naumann G (July 1975). "[Treatment of hypertonus in diabetes mellitus]". Zeitschrift für die Gesamte Innere Medizin und Ihre Grenzgebiete. 30 (13): 437–442. PMID 4929.
• Perlmann T, Jansson L (April 1995). "A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1". Genes & Development. 9 (7): 769–782. doi:10.1101/gad.9.7.769. PMID 7705655.
• Forman BM, Umesono K, Chen J, Evans RM (May 1995). "Unique response pathways are established by allosteric interactions among nuclear hormone receptors". Cell. 81 (4): 541–550. doi:10.1016/0092-8674(95)90075-6. PMID 7758108. S2CID 3203590.
• Mages HW, Rilke O, Bravo R, Senger G, Kroczek RA (November 1994). "NOT, a human immediate-early response gene closely related to the steroid/thyroid hormone receptor NAK1/TR3". Molecular Endocrinology. 8 (11): 1583–1591. doi:10.1210/mend.8.11.7877627. PMID 7877627.
• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Torii T, Kawarai T, Nakamura S, Kawakami H (April 1999). "Organization of the human orphan nuclear receptor Nurr1 gene". Gene. 230 (2): 225–232. doi:10.1016/S0378-1119(99)00064-5. PMID 10216261.
• Ichinose H, Ohye T, Suzuki T, Sumi-Ichinose C, Nomura T, Hagino Y, et al. (April 1999). "Molecular cloning of the human Nurr1 gene: characterization of the human gene and cDNAs". Gene. 230 (2): 233–239. doi:10.1016/S0378-1119(99)00065-7. PMID 10216262.
• Chen YH, Tsai MT, Shaw CK, Chen CH (December 2001). "Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in schizophrenic patients". American Journal of Medical Genetics. 105 (8): 753–757. doi:10.1002/ajmg.10036. PMID 11803525.
• Ishiguro H, Okubo Y, Ohtsuki T, Yamakawa-Kobayashi K, Arinami T (January 2002). "Mutation analysis of the retinoid X receptor beta, nuclear-related receptor 1, and peroxisome proliferator-activated receptor alpha genes in schizophrenia and alcohol dependence: possible haplotype association of nuclear-related receptor 1 gene to alcohol dependence". American Journal of Medical Genetics. 114 (1): 15–23. doi:10.1002/ajmg.1620. PMID 11840500.
• McEvoy AN, Murphy EA, Ponnio T, Conneely OM, Bresnihan B, FitzGerald O, et al. (March 2002). "Activation of nuclear orphan receptor NURR1 transcription by NF-kappa B and cyclic adenosine 5'-monophosphate response element-binding protein in rheumatoid arthritis synovial tissue". Journal of Immunology. 168 (6): 2979–2987. doi:10.4049/jimmunol.168.6.2979. PMID 11884470.
• Xu PY, Liang R, Jankovic J, Hunter C, Zeng YX, Ashizawa T, et al. (March 2002). "Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson's disease". Neurology. 58 (6): 881–884. doi:10.1212/wnl.58.6.881. PMID 11914402. S2CID 19632736.
• Bannon MJ, Pruetz B, Manning-Bog AB, Whitty CJ, Michelhaugh SK, Sacchetti P, et al. (April 2002). "Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers". Proceedings of the National Academy of Sciences of the United States of America. 99 (9): 6382–6385. Bibcode:2002PNAS...99.6382B. doi:10.1073/pnas.092654299. PMC 122957. PMID 11959923.
• Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, et al. (January 2003). "Mutations in NR4A2 associated with familial Parkinson disease". Nature Genetics. 33 (1): 85–89. doi:10.1038/ng1066. PMID 12496759. S2CID 10699494.
• Satoh J, Kuroda Y (December 2002). "The constitutive and inducible expression of Nurr1, a key regulator of dopaminergic neuronal differentiation, in human neural and non-neural cell lines". Neuropathology. 22 (4): 219–232. doi:10.1046/j.1440-1789.2002.00460.x. PMID 12564761. S2CID 30708166.
• Iwayama-Shigeno Y, Yamada K, Toyota T, Shimizu H, Hattori E, Yoshitsugu K, et al. (April 2003). "Distribution of haplotypes derived from three common variants of the NR4A2 gene in Japanese patients with schizophrenia". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 118B (1): 20–24. doi:10.1002/ajmg.b.10053. PMID 12627459. S2CID 35675105.
• Kim KS, Kim CH, Hwang DY, Seo H, Chung S, Hong SJ, et al. (May 2003). "Orphan nuclear receptor Nurr1 directly transactivates the promoter activity of the tyrosine hydroxylase gene in a cell-specific manner". Journal of Neurochemistry. 85 (3): 622–634. doi:10.1046/j.1471-4159.2003.01671.x. PMID 12694388. S2CID 6219768.
• Ramos LL, Monteiro FP, Sampaio LP, Costa LA, Ribeiro MD, Freitas EL, et al. (August 2019). "Heterozygous loss of function of NR4A2 is associated with intellectual deficiency, rolandic epilepsy, and language impairment". Clinical Case Reports. 7 (8): 1582–1584. doi:10.1002/ccr3.2260. PMC 6693049. PMID 31428396.

External links

• Nurr1+nuclear+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)