Nuclear receptor 4A2 explained

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.^[1] NR4A2 is a member of the nuclear receptor family of intracellular transcription factors.

NR4A2 plays a key role in the maintenance of the dopaminergic system of the brain.^[2] 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.^[3]

This protein is thought to be critical to development of the dopamine phenotype in the midbrain, as mice without NR4A2 are lacking expression of this phenotype. This is further confirmed by studies showing that when forcing NR4A2 expression in naïve precursor cells, there is complete dopamine phenotype gene expression.^[4]

While NR4A2 is a key protein, there are other factors required as research shows that solely expressing NR4A2 fails to stimulate this phenotypic gene expression. 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, both of these factors were present in order to have expression for the dopamine phenotype.

NR4A2 and Developmental Disorders

Mutations in NR4A2 have been associated with various developmental disorders, including Parkinson disease, schizophrenia, manic depression, and autism. De novo 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.^[5]

NR4A2 and 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 CNS 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 for NR4A2 was expressed in microglia and astrocytes, these cells produced inflammatory mediators, such as TNFa, NO synthase and 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-modifying enzymes. The NR4A2/CoREST complex inhibits transcription of inflammatory genes.^[6]

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.^[7]

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.^[8] 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.

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.^[9]

Interactions

NR4A2 has been shown to interact with:

• Beta-catenin,^[10]
• Pituitary homeobox 3,^[11]
• Retinoic acid receptor alpha,^[12] and
• Retinoic acid receptor beta.^[12]

Further reading

• Le W, Appel SH . Mutant genes responsible for Parkinson's disease . Current Opinion in Pharmacology . 4 . 1 . 79–84 . February 2004 . 15018843 . 10.1016/j.coph.2003.09.005 .
• Wedler B, Wüstenberg PW, Naumann G . [Treatment of hypertonus in diabetes mellitus] . Zeitschrift für die Gesamte Innere Medizin und Ihre Grenzgebiete . 30 . 13 . 437–442 . July 1975 . 4929 .
• Perlmann T, Jansson L . A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1 . Genes & Development . 9 . 7 . 769–782 . April 1995 . 7705655 . 10.1101/gad.9.7.769 . free .
• Forman BM, Umesono K, Chen J, Evans RM . Unique response pathways are established by allosteric interactions among nuclear hormone receptors . Cell . 81 . 4 . 541–550 . May 1995 . 7758108 . 10.1016/0092-8674(95)90075-6 . 3203590 . free .
• Mages HW, Rilke O, Bravo R, Senger G, Kroczek RA . NOT, a human immediate-early response gene closely related to the steroid/thyroid hormone receptor NAK1/TR3 . Molecular Endocrinology . 8 . 11 . 1583–1591 . November 1994 . 7877627 . 10.1210/mend.8.11.7877627 . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–174 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–156 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Torii T, Kawarai T, Nakamura S, Kawakami H . Organization of the human orphan nuclear receptor Nurr1 gene . Gene . 230 . 2 . 225–232 . April 1999 . 10216261 . 10.1016/S0378-1119(99)00064-5 .
• Ichinose H, Ohye T, Suzuki T, Sumi-Ichinose C, Nomura T, Hagino Y, Nagatsu T . Molecular cloning of the human Nurr1 gene: characterization of the human gene and cDNAs . Gene . 230 . 2 . 233–239 . April 1999 . 10216262 . 10.1016/S0378-1119(99)00065-7 .
• Chen YH, Tsai MT, Shaw CK, Chen CH . 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 . December 2001 . 11803525 . 10.1002/ajmg.10036 .
• Ishiguro H, Okubo Y, Ohtsuki T, Yamakawa-Kobayashi K, Arinami T . 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 . January 2002 . 11840500 . 10.1002/ajmg.1620 .
• McEvoy AN, Murphy EA, Ponnio T, Conneely OM, Bresnihan B, FitzGerald O, Murphy EP . 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 . March 2002 . 11884470 . 10.4049/jimmunol.168.6.2979 . free .
• Xu PY, Liang R, Jankovic J, Hunter C, Zeng YX, Ashizawa T, Lai D, Le WD . 6 . Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson's disease . Neurology . 58 . 6 . 881–884 . March 2002 . 11914402 . 10.1212/wnl.58.6.881 . 19632736 .
• Bannon MJ, Pruetz B, Manning-Bog AB, Whitty CJ, Michelhaugh SK, Sacchetti P, Granneman JG, Mash DC, Schmidt CJ . 6 . 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 . April 2002 . 11959923 . 122957 . 10.1073/pnas.092654299 . free . 2002PNAS...99.6382B .
• Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK . Mutations in NR4A2 associated with familial Parkinson disease . Nature Genetics . 33 . 1 . 85–89 . January 2003 . 12496759 . 10.1038/ng1066 . 10699494 .
• Satoh J, Kuroda Y . 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 . December 2002 . 12564761 . 10.1046/j.1440-1789.2002.00460.x . 30708166 .
• Iwayama-Shigeno Y, Yamada K, Toyota T, Shimizu H, Hattori E, Yoshitsugu K, Fujisawa T, Yoshida Y, Kobayashi T, Toru M, Kurumaji A, Detera-Wadleigh S, Yoshikawa T . 6 . 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 . April 2003 . 12627459 . 10.1002/ajmg.b.10053 . 35675105 . free .
• Kim KS, Kim CH, Hwang DY, Seo H, Chung S, Hong SJ, Lim JK, Anderson T, Isacson O . 6 . 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 . May 2003 . 12694388 . 10.1046/j.1471-4159.2003.01671.x . 6219768 . free .
• Ramos LL, Monteiro FP, Sampaio LP, Costa LA, Ribeiro MD, Freitas EL, Kitajima JP, Kok F . 6 . Heterozygous loss of function of NR4A2 is associated with intellectual deficiency, rolandic epilepsy, and language impairment . Clinical Case Reports . 7 . 8 . 1582–1584 . August 2019 . 31428396 . 10.1002/ccr3.2260 . 6693049 .

Notes and References

1. Okabe T, Takayanagi R, Imasaki K, Haji M, Nawata H, Watanabe T . cDNA cloning of a NGFI-B/nur77-related transcription factor from an apoptotic human T cell line . Journal of Immunology . 154 . 8 . 3871–3879 . April 1995 . 10.4049/jimmunol.154.8.3871 . 7706727 . 36075352 . free .
2. Sacchetti P, Carpentier R, Ségard P, Olivé-Cren C, Lefebvre P . Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor NURR1 . Nucleic Acids Research . 34 . 19 . 5515–5527 . 2006 . 17020917 . 1636490 . 10.1093/nar/gkl712 .
3. Web site: Entrez Gene: NR4A2 nuclear receptor subfamily 4, group A, member 2.
4. Yi SH, He XB, Rhee YH, Park CH, Takizawa T, Nakashima K, Lee SH . Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation . Development . 141 . 4 . 761–772 . February 2014 . 24496614 . 10.1242/dev.095802 . 16677797 . free .
5. Web site: Barge-Schaapveld, Leppa, Reuter . Gene: NR4a2 - . SFARI GENE . 16 January 2023.
6. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK . 6 . A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death . Cell . 137 . 1 . 47–59 . April 2009 . 19345186 . 2754279 . 10.1016/j.cell.2009.01.038 .
7. Codina A, Benoit G, Gooch JT, Neuhaus D, Perlmann T, Schwabe JW . Identification of a novel co-regulator interaction surface on the ligand binding domain of Nurr1 using NMR footprinting . The Journal of Biological Chemistry . 279 . 51 . 53338–53345 . December 2004 . 15456745 . 10.1074/jbc.M409096200 . free .
8. Kim JY, Koh HC, Lee JY, Chang MY, Kim YC, Chung HY, Son H, Lee YS, Studer L, McKay R, Lee SH . 6 . Dopaminergic neuronal differentiation from rat embryonic neural precursors by Nurr1 overexpression . Journal of Neurochemistry . 85 . 6 . 1443–1454 . June 2003 . 12787064 . 10.1046/j.1471-4159.2003.01780.x . 21991471 . free .
9. Zhang L, Le W, Xie W, Dani JA . Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson's disease . Neurobiology of Aging . 33 . 5 . 1001.e7–1001.16 . May 2012 . 21531044 . 3155628 . 10.1016/j.neurobiolaging.2011.03.022 .
10. Zhang L, Cen L, Qu S, Wei L, Mo M, Feng J, Sun C, Xiao Y, Luo Q, Li S, Yang X, Xu P . 6 . Enhancing Beta-Catenin Activity via GSK3beta Inhibition Protects PC12 Cells against Rotenone Toxicity through Nurr1 Induction . PLOS ONE . 11 . 4 . e0152931 . Apr 2016 . 27045591 . 4821554 . 10.1371/journal.pone.0152931 . free . 2016PLoSO..1152931Z .
11. Jacobs FM, van Erp S, van der Linden AJ, von Oerthel L, Burbach JP, Smidt MP . Pitx3 potentiates Nurr1 in dopamine neuron terminal differentiation through release of SMRT-mediated repression . Development . 136 . 4 . 531–540 . February 2009 . 19144721 . 10.1242/dev.029769 . 5989601 .
12. Perlmann T, Jansson L . A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1 . Genes & Development . 9 . 7 . 769–782 . April 1995 . 7705655 . 10.1101/gad.9.7.769 . free .