Alternative titles; symbols
HGNC Approved Gene Symbol: NR2F6
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:17,231,883-17,245,919 (from NCBI)
Miyajima et al. (1988) identified in the human genome 2 ERBA-related genes, named EAR2 and EAR3 (132890), and characterized them by cDNA cloning. The genes are predicted to encode proteins very similar in primary structure to receptors for steroid hormones and thyroid hormone. In addition, the amino acid sequences of the 2 gene products are very similar to each other, especially in the DNA-binding domain (86% homology) and at the putative ligand-binding domain (76% homology). Northern hybridization using EAR DNA probes with RNAs from various tissues of the human fetus showed that the expression of EAR2 is high in the liver, whereas the expression of EAR3 is relatively ubiquitous.
By hybridization analysis of DNAs from sorted chromosomes, Miyajima et al. (1988) showed that the EAR2 gene is located on chromosome 19 and the EAR3 gene on chromosome 5.
Bahler et al. (1997) performed cosmid contig mapping indicating that the NR2F6 gene was 100 kb proximal to MYO9B (602129) on chromosome 19p13.1.
By yeast 1-hybrid screen and in vitro assays of recombinant mouse Ear2, Liu et al. (2003) determined that Ear2 specifically binds the TGACCT direct-repeat motif. Overexpression of Ear2 in mouse kidney tumor cells showed that Ear2 potently decreased both baseline and retinoid-induced mouse renin promoter activity in a dose-dependent, enhancer-dependent, and sequence-specific manner. Mutations in Ear2, which abolished binding to the TGACCT motif, also abolished transcriptional repression.
By in silico and biochemical analyses, Hermann-Kleiter et al. (2008) identified ser83 on NR2F6 as a substrate for protein kinase C (PKC; see 176960). NR2F6 potently antagonized the ability of mouse Th0 and Th17 cells to induce expression of cytokines, including Il2 (147680) and Il17 (IL17A; 603149). NR2F6 interfered with DNA binding by the NFAT (see 600490)/AP1 (165160) complex, but not NF-kappa-B (see 164011) and, subsequently, transcriptional activity of the NFAT-dependent IL17A promoter. Based on these findings and findings in Nr2f6 -/- mice (see ANIMAL MODEL), Hermann-Kleiter et al. (2008) concluded that NR2F6 is a transcriptional repressor of IL17 expression in Th17-differentiated CD4-positive T cells in vitro and in vivo.
Warnecke et al. (2005) found that Nr2f6-null mice were born at expected mendelian ratios, but they showed defects in development of the locus ceruleus (LC). Examination of the genes expressed in the LC of Nr2f6-null mice suggested that Nr2f6 resides in a signaling cascade leading to LC development that operates in the order Mash1 (ASCL1; 100790)--Nr2f6--Phox2b (603851)--Phox2a (ARIX; 602753). More than 70% of LC neurons were absent in Nr2f6-null adults, with agenesis affecting primarily the dorsal division of the LC, which normally projects noradrenergic efferents to the cortex. In agreement with this, the cortical concentration of noradrenalin was reduced 4-fold in mutant mice. The defects in the LC of mutant mice were also associated with defects in circadian behaviors and circadian gene expression. Warnecke et al. (2005) concluded that NR2F6 is required early in the development of the LC. They proposed that neurons in the dorsal division of the LC contribute to the regulation of the forebrain clock, at least in part, through targeted release of noradrenalin into the cortical area.
Hermann-Kleiter et al. (2008) found that mice lacking Nr2f6 had hyperactive lymphocytes, developed late-onset immunopathology, and were hypersusceptible to Th17-dependent experimental autoimmune encephalomyelitis.
Bahler, M., Kehrer, I., Gordon, L., Stoffler, H.-E., Olsen, A. S. Physical mapping of human myosin-IXB (MYO9B), the human orthologue of the rat myosin myr 5, to chromosome 19p13.1. Genomics 43: 107-109, 1997. [PubMed: 9226381] [Full Text: https://doi.org/10.1006/geno.1997.4776]
Hermann-Kleiter, N., Gruber, T., Lutz-Nicoladoni, C., Thuille, N., Fresser, F., Labi, V., Schiefermeier, N., Warnecke, M., Huber, L., Villunger, A., Eichele, G., Kaminski, S., Baier, G. The nuclear orphan receptor NR2F6 suppresses lymphocyte activation and T helper 17-dependent autoimmunity. Immunity 29: 205-216, 2008. [PubMed: 18701084] [Full Text: https://doi.org/10.1016/j.immuni.2008.06.008]
Liu, X., Huang, X., Sigmund, C. D. Identification of a nuclear orphan receptor (Ear2) as a negative regulator of renin gene transcription. Circ. Res. 92: 1033-1040, 2003. [PubMed: 12690040] [Full Text: https://doi.org/10.1161/01.RES.0000071355.82009.43]
Miyajima, N., Kadowaki, Y., Fukushige, S., Shimizu, S., Semba, K., Yamanashi, Y., Matsubara, K., Toyoshima, K., Yamamoto, T. Identification of two novel members of erbA superfamily by molecular cloning: the gene products of the two are highly related to each other. Nucleic Acids Res. 16: 11057-11073, 1988. [PubMed: 2905047] [Full Text: https://doi.org/10.1093/nar/16.23.11057]
Warnecke, M., Oster, H., Revelli, J.-P., Alvarez-Bolado, G., Eichele, G. Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception. Genes Dev. 19: 614-625, 2005. [PubMed: 15741322] [Full Text: https://doi.org/10.1101/gad.317905]