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

NR4A2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNR4A2, HZF-3, NOT, NURR1, RNR1, TINUR, nuclear receptor subfamily 4 group A member 2
External IDsOMIM: 601828 MGI: 1352456 HomoloGene: 4509 GeneCards: NR4A2
Orthologs
SpeciesHumanMouse
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 MbChr 2: 57 – 57.01 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

NR4A2 plays a key role in the maintenance of the dopaminergic system of the brain.[6] 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.[7]

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.[8]

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. [8]

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.[9]

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.[10]

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.[11]

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.[12] 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.[13]

Interactions

NR4A2 has been shown to interact with:

References
  1. GRCh38: Ensembl release 89: ENSG00000153234 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000026826 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Okabe T, Takayanagi R, Imasaki K, Haji M, Nawata H, Watanabe T (April 1995). "cDNA cloning of a NGFI-B/nur77-related transcription factor from an apoptotic human T cell line". Journal of Immunology. 154 (8): 3871–3879. doi:10.4049/jimmunol.154.8.3871. PMID 7706727. S2CID 36075352.
  6. Sacchetti P, Carpentier R, Ségard P, Olivé-Cren C, Lefebvre P (2006). "Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor NURR1". Nucleic Acids Research. 34 (19): 5515–5527. doi:10.1093/nar/gkl712. PMC 1636490. PMID 17020917.
  7. "Entrez Gene: NR4A2 nuclear receptor subfamily 4, group A, member 2".
  8. Yi SH, He XB, Rhee YH, Park CH, Takizawa T, Nakashima K, Lee SH (February 2014). "Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation". Development. 141 (4): 761–772. doi:10.1242/dev.095802. PMID 24496614. S2CID 16677797.
  9. Barge-Schaapveld, Leppa, Reuter. "Gene: NR4a2 -". SFARI GENE. Retrieved 16 January 2023.
  10. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, et al. (April 2009). "A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death". Cell. 137 (1): 47–59. doi:10.1016/j.cell.2009.01.038. PMC 2754279. PMID 19345186.
  11. Codina A, Benoit G, Gooch JT, Neuhaus D, Perlmann T, Schwabe JW (December 2004). "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. doi:10.1074/jbc.M409096200. PMID 15456745.
  12. Kim JY, Koh HC, Lee JY, Chang MY, Kim YC, Chung HY, et al. (June 2003). "Dopaminergic neuronal differentiation from rat embryonic neural precursors by Nurr1 overexpression". Journal of Neurochemistry. 85 (6): 1443–1454. doi:10.1046/j.1471-4159.2003.01780.x. PMID 12787064. S2CID 21991471.
  13. Zhang L, Le W, Xie W, Dani JA (May 2012). "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. doi:10.1016/j.neurobiolaging.2011.03.022. PMC 3155628. PMID 21531044.
  14. Zhang L, Cen L, Qu S, Wei L, Mo M, Feng J, et al. (Apr 2016). "Enhancing Beta-Catenin Activity via GSK3beta Inhibition Protects PC12 Cells against Rotenone Toxicity through Nurr1 Induction". PLOS ONE. 11 (4): e0152931. Bibcode:2016PLoSO..1152931Z. doi:10.1371/journal.pone.0152931. PMC 4821554. PMID 27045591.
  15. Jacobs FM, van Erp S, van der Linden AJ, von Oerthel L, Burbach JP, Smidt MP (February 2009). "Pitx3 potentiates Nurr1 in dopamine neuron terminal differentiation through release of SMRT-mediated repression". Development. 136 (4): 531–540. doi:10.1242/dev.029769. PMID 19144721.
  16. 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.

Further reading
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