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Target not currently curated in GtoImmuPdb
Target id: 617
Nomenclature: COUP-TF1
Systematic Nomenclature: NR2F1
Family: 2F. COUP-TF-like receptors
Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 423 | 5q15 | NR2F1 | nuclear receptor subfamily 2 group F member 1 | 32 |
| Mouse | 422 | 13 41.38 cM | Nr2f1 | nuclear receptor subfamily 2, group F, member 1 | 21 |
| Rat | 419 | 2q11 | Nr2f1 | nuclear receptor subfamily 2, group F, member 1 | 6 |
| Previous and Unofficial Names |
| COUPα | EAR3 | SVP44 | ERBAL3 | TFCOUP1 | nuclear receptor subfamily 2 |
| Database Links |
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| Alphafold | P10589 (Hs), Q60632 (Mm) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL1961789 (Hs) |
| Ensembl Gene | ENSG00000175745 (Hs), ENSMUSG00000069171 (Mm), ENSRNOG00000014795 (Rn) |
| Entrez Gene | 7025 (Hs), 13865 (Mm), 81808 (Rn) |
| Human Protein Atlas | ENSG00000175745 (Hs) |
| KEGG Gene | hsa:7025 (Hs), mmu:13865 (Mm), rno:81808 (Rn) |
| OMIM | 132890 (Hs) |
| Pharos | P10589 (Hs) |
| RefSeq Nucleotide | NM_005654 (Hs), NM_010151 (Mm), NM_031130 (Rn) |
| RefSeq Protein | NP_005645 (Hs), NP_034281 (Mm), NP_112392 (Rn) |
| UniProtKB | P10589 (Hs), Q60632 (Mm) |
| Wikipedia | NR2F1 (Hs) |
| Natural/Endogenous Ligands |
| Comments: Orphan |
| DNA Binding |
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| DNA Binding Comments | |||||||
| Heterodimerization with RXR in solution is still a controversial issue. However, COUP-TFs readily form DNA-binding heterodimers with RXR. COUP-TFI is able to heterodimerize with COUP-TFII. Systematic comparison of the relative affinities of COUP-TFs for the various elements reveal that DR1 is the preferred element and then DR6, DR4, DR8, DR0 and DR11. Palindromic and inverted repeats are also recognised but with a lower affinity. In contrast, monomeric elements are not efficiently recognised by COUP-TFs. It has been demonstrated that COUP-TFs repress the hormonal induction of target genes by PPAR, VDR, TR, and RAR in transient transfection assays through direct competition with VDR, TR, and RAR for the available binding sites. | |||||||
| Co-binding Partners |
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| Name | Interaction | Effect | Reference |
| Retinoid X receptor-β | Physical, Functional | COUP-TFs are able to sequester the common heterodimerization partner RXR and reduce the available concentrations of RXR. The loss of RXR indirectly decreases the DNA-binding affinity of TR, VDR, RAR, and PPAR and thereby interferes with the potential of this subgroup of receptors to transactivate their target genes. | 7-8,10,31 |
| Hepatocyte nuclear factor-4-α | Physical, Functional | COUP-TF interact both functionally and physically with the NRs HNF4. COUP-TFs have been shown to inhibit the transactivation of HNF4 due to mutually exclusive binding to the promoter of many genes. In addition, COUP-TF activates transcription through protein-protein interaction with DNA-bound factor, such as with HNF-4 in the HNF-1a gene promoter. Similar mechanism are observed for other transcription factor (Sp1). | 11,24,28 |
| Thyroid hormone receptor-α | Physical, Functional | COUP-TFs:TR heterodimerization interfere with TR dependent transcriptional regulation. | 7,12 |
| Retinoic acid receptor-α | Physical, Functional | COUP-TFs:RAR heterodimerization interfere with RAR dependent transcriptional regulation. | 7,12 |
| Estrogen receptor-α | Physical, Functional | the formation of a tight ERa-COUP-TFI intermediate complex through COUP-TFI DBD and ER LBD resulted in an increased recruitment of ERK2/p42 MAPK, phosphorylation of the hERa on Ser 118 and enhanced its transcriptional activity. In addition, COUP-TF has been shown to antagonize ER activation of the lactoferrin and oxytocin promoters by binding to a binding site that overlaps with the estrogen response element. | 14,17 |
| BCL11A | Physical, Functional | COUP-TFs ligand binding domain interacts with BCL11A to repress its endogenous target γ-globin nand Bgl3 genes | 3,5 |
| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| NCOR1 | Co-repressor | No | No | No | 26 | |
| NCOR2 | Co-repressor | No | No | No | 26 | |
| NCOA1 | Co-activator | No | No | Yes | 28 | |
| BCL11A | Co-repressor | Yes | No | Yes | transcriptional repression mediated by COUP-TF acting through CTIP1 did not appear to involve recruitment of a trichostatin A-sensitive histone deacetylase to the template, suggesting that this repression pathway may be distinct from that utilized by several other nuclear receptors. | 3 |
| BCL11B | Co-repressor | No | No | Yes | transcriptional repression mediated by COUP-TF acting through CTIP1 did not appear to involve recruitment of a trichostatin A-sensitive histone deacetylase to the template, suggesting that this repression pathway may be distinct from that utilized by several other nuclear receptors. | 3 |
| CREBBP | Co-activator | No | No | Yes | COUP-TFI also interacts with EP300 also known as p300. | 20 |
| Main Target Genes |
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| Name | Species | Effect | Technique | Comments | References |
| Nr4a1 | Rat | Activated | Transient transfection, EMSA, Other | COUP TFI positively regulates the NGFI-A gene via aprotein-protein interaction with DNA bound Sp1. | 20 |
| MHC Class I | Mouse | Repressed | Transient transfection, EMSA | COUP-TFs directly inhibits MHC Class I expression via interaction with the R2 promoter element and recruitment of the NCoR and HDACs. | 13 |
| CYP3A1 | Human | Repressed | Transient transfection, EMSA, Other | COUP-TFs repressed the CYP3A1 gene expression by interacting with HNF4 (see in all species) | 19 |
| PEPCK | Human | Activated | Transient transfection, EMSA | COUP-TF binds to the AF1 element and function as accessory factors for the glucocorticoid response of the PEPCK gene ( activated in all species) | 9,25 |
| Transferrin | Human | Both | Transient transfection, EMSA, Other | COUP-TF1 alone or in combination with HNF4 activates or repress Transferrin gene expression respectively. | 24 |
| SOX9 | Human | Activated | Transient transfection, luciferase assay | COUP TFs positively regulates the Sox9 gene to control tumor cell dormancy and mesenchymal cell development. This is also seen in mouse. | 27,33 |
| Pax6 | Mouse | Repressed | ChIP, Transient transfection | COUP TFI represses the Pax6 gene to control eye development. | 29 |
| Otx2 | Mouse | Activated | ChIP, Transient transfection | COUP TFs activate the Pax6 gene via a protein-protein interaction with DNA bound Sp1. | 29 |
| Fabp7 | Mouse | Activated | ChIP, Transient transfection | Fabp7 is a direct COUP-TFI target in inner ear. | 16 |
| Rnd2 | Mouse | Repressed | ChIP | COUP-TFI directly represses Rnd2 expression during mouse corticogenesis. | 1 |
| Main Target Genes Comments | |||||
| COUP-TF I mutation has been associated with individuals with cerebral visual impairment and/or optic nerve abnormalities [4]. | |||||
| Tissue Distribution Comments | |
| In human COUP-TFI is expressed as two transcripts of 4.6 and 4.8 kb that show a broad expression pattern. In mice, COUP-TFI expression was first detected at 7.5 dpc, peaked at 14-15 days dpc and strongly declined before birth when organogenesis stops. At 8.5 dpc COUP-TFI is expressed in specific regions of the rostral brain, in stripes in the presumptive hindbrain as well as in the anterior somites. Later on, it exhibits a more complex expression pattern in CNS which is clearly different from the one of COUP-TFII. COUP-TFI is expressed throughout the neural tube with a small increased level in motoneurons. The expression appears also restricted in other organs and is always weaker than the one of COUP-TFII. COUP-TFI is found at high levels in the tongue, the follicles of the vibrissae, the cochlea and in the nasal septum stroma. In organs that requires mesenchymal and epithelial interactions, COUP-TFI is expressed in the mesenchymal cells, but not in the terminally differentiated epithelium. In adult, the expression is strongly reduced and COUP-TFI was found in the rostral and caudal part of the mouse brain, in particular in the supraoptic nucleus [3,20-21]. |
| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| These animals exhibit defects in morphogenesis of the ninth cranial ganglion and nerve resulting from an excess cell death in the ganglionic precursor cells. In addition axonal guidance and arborization defects were noticed in several regions. This results in a fewer number of cells in the ninth ganglia and abnormal nerve projections toward the hindbrain. Since the ninth ganglia supplies sensory and motor innervation to the pharynx and root of the tongue as well as to the ear and soft palate this may explain the inability of the mutant animals to obtain exogenous nutriments and there death by starvation and dehydratation. In addition COUP-TFI mutants have axon guidance defect which results in the thanlamocortical axon could not reach cortex to innervate neurons in layer IV and to maintain layer IV neuron survival. Furthermore, COUP-TFI mutants has brain regionalization defect. COUP-TFI is one of the regulatory genes that control the expression of genes important for brain regionalization. Finally, COUP-TFI is important for axon myelination. Without it oligodendrocytes cannot differentiation properly. Numerous studies over past decades unequivocally demonstrate that COUP-TFs are key players dictating the development of neural stem/progenitor cells (NSPC) at various subareas of central nervous system (CNS). First, COUP-TFs are intrinsic factors defining the competence of NSPCs and COUP-TFs are required for the gliogenic competence and neuropotency of neural precursor cells in the CNS development [18]. Second, COUP-TFI gene determines the spatial specification of NSPC as COUP-TFI controls the early neocortical regionalization [36]. Further analyses using the dorsal telencephalon specific COUP-TFI knockout indicate that COUP-TFI is necessary for the cortical patterning between frontal/motor and sensory areas [2]. COUP-TFs also define diverse cell fates during NSPCs development. In Emx1Cre mediated COUP-TFI-deficient mice, the corticospinal motor neurons in the somatosensory cortex do not develop properly [30]. Another mutant mouse, having COUP-TFI depleted in the subventricular precursors and postmitotic cells, shows a decrease in late-born, caudal ganglionic eminence (CGE)-derived cortical interneuons with the concomitant augment of early-born cortical interneurons originated from medial ganglionic eminence (MGE) [15]. In addition, COUP-TFI and COUP-TFII coordinately modulates the proliferation, migration and survival of granule cells in the olfactory bulb [37]. Moreover, COUP-TF transcriptional factors are present in dorsal or ventral retinal neural stem cells and direct appropriate neural retina development [23,29]. |
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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1. Alfano C, Viola L, Heng JI, Pirozzi M, Clarkson M, Flore G, De Maio A, Schedl A, Guillemot F, Studer M. (2011) COUP-TFI promotes radial migration and proper morphology of callosal projection neurons by repressing Rnd2 expression. Development, 138 (21): 4685-97. [PMID:21965613]
2. Armentano M, Chou SJ, Tomassy GS, Leingärtner A, O'Leary DD, Studer M. (2007) COUP-TFI regulates the balance of cortical patterning between frontal/motor and sensory areas. Nat Neurosci, 10 (10): 1277-86. [PMID:17828260]
3. Avram D, Fields A, Pretty On Top K, Nevrivy DJ, Ishmael JE, Leid M. (2000) Isolation of a novel family of C(2)H(2) zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors. J Biol Chem, 275 (14): 10315-22. [PMID:10744719]
4. Bosch DG, Boonstra FN, Gonzaga-Jauregui C, Xu M, de Ligt J, Jhangiani S, Wiszniewski W, Muzny DM, Yntema HG, Pfundt R et al.. (2014) NR2F1 mutations cause optic atrophy with intellectual disability. Am J Hum Genet, 94 (2): 303-9. [PMID:24462372]
5. Chan CM, Fulton J, Montiel-Duarte C, Collins HM, Bharti N, Wadelin FR, Moran PM, Mongan NP, Heery DM. (2013) A signature motif mediating selective interactions of BCL11A with the NR2E/F subfamily of orphan nuclear receptors. Nucleic Acids Res, 41 (21): 9663-79. [PMID:23975195]
6. Connor H, Nornes H, Neuman T. (1995) Expression screening reveals an orphan receptor chick ovalbumin upstream promoter transcription factor I as a regulator of neurite/substrate-cell contacts and cell aggregation. J Biol Chem, 270 (25): 15066-70. [PMID:7797489]
7. Cooney AJ, Leng X, Tsai SY, O'Malley BW, Tsai MJ. (1993) Multiple mechanisms of chicken ovalbumin upstream promoter transcription factor-dependent repression of transactivation by the vitamin D, thyroid hormone, and retinoic acid receptors. J Biol Chem, 268 (6): 4152-60. [PMID:8382695]
8. Cooney AJ, Tsai SY, O'Malley BW, Tsai MJ. (1992) Chicken ovalbumin upstream promoter transcription factor (COUP-TF) dimers bind to different GGTCA response elements, allowing COUP-TF to repress hormonal induction of the vitamin D3, thyroid hormone, and retinoic acid receptors. Mol Cell Biol, 12 (9): 4153-63. [PMID:1324415]
9. Hall RK, Sladek FM, Granner DK. (1995) The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. Proc Natl Acad Sci USA, 92 (2): 412-6. [PMID:7831301]
10. Kliewer SA, Umesono K, Heyman RA, Mangelsdorf DJ, Dyck JA, Evans RM. (1992) Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling. Proc Natl Acad Sci USA, 89 (4): 1448-52. [PMID:1311101]
11. Ktistaki E, Talianidis I. (1997) Chicken ovalbumin upstream promoter transcription factors act as auxiliary cofactors for hepatocyte nuclear factor 4 and enhance hepatic gene expression. Mol Cell Biol, 17 (5): 2790-7. [PMID:9111350]
12. Leng X, Cooney AJ, Tsai SY, Tsai MJ. (1996) Molecular mechanisms of COUP-TF-mediated transcriptional repression: evidence for transrepression and active repression. Mol Cell Biol, 16 (5): 2332-40. [PMID:8628300]
13. Liu X, Ge R, Westmoreland S, Cooney AJ, Tsai SY, Tsai MJ, Ricciardi RP. (1994) Negative regulation by the R2 element of the MHC class I enhancer in adenovirus-12 transformed cells correlates with high levels of COUP-TF binding. Oncogene, 9 (8): 2183-90. [PMID:8036004]
14. Liu Y, Yang N, Teng CT. (1993) COUP-TF acts as a competitive repressor for estrogen receptor-mediated activation of the mouse lactoferrin gene. Mol Cell Biol, 13 (3): 1836-46. [PMID:8441416]
15. Lodato S, Tomassy GS, De Leonibus E, Uzcategui YG, Andolfi G, Armentano M, Touzot A, Gaztelu JM, Arlotta P, Menendez de la Prida L et al.. (2011) Loss of COUP-TFI alters the balance between caudal ganglionic eminence- and medial ganglionic eminence-derived cortical interneurons and results in resistance to epilepsy. J Neurosci, 31 (12): 4650-62. [PMID:21430164]
16. Montemayor C, Montemayor OA, Ridgeway A, Lin F, Wheeler DA, Pletcher SD, Pereira FA. (2010) Genome-wide analysis of binding sites and direct target genes of the orphan nuclear receptor NR2F1/COUP-TFI. PLoS ONE, 5 (1): e8910. [PMID:20111703]
17. Métivier R, Gay FA, Hübner MR, Flouriot G, Salbert G, Gannon F, Kah O, Pakdel F. (2002) Formation of an hER alpha-COUP-TFI complex enhances hER alpha AF-1 through Ser118 phosphorylation by MAPK. EMBO J, 21 (13): 3443-53. [PMID:12093745]
18. Naka H, Nakamura S, Shimazaki T, Okano H. (2008) Requirement for COUP-TFI and II in the temporal specification of neural stem cells in CNS development. Nat Neurosci, 11 (9): 1014-23. [PMID:19160499]
19. Ogino M, Nagata K, Miyata M, Yamazoe Y. (1999) Hepatocyte nuclear factor 4-mediated activation of rat CYP3A1 gene and its modes of modulation by apolipoprotein AI regulatory protein I and v-ErbA-related protein 3. Arch Biochem Biophys, 362 (1): 32-7. [PMID:9917326]
20. Pipaón C, Tsai SY, Tsai MJ. (1999) COUP-TF upregulates NGFI-A gene expression through an Sp1 binding site. Mol Cell Biol, 19 (4): 2734-45. [PMID:10082539]
21. Qiu Y, Cooney AJ, Kuratani S, DeMayo FJ, Tsai SY, Tsai MJ. (1994) Spatiotemporal expression patterns of chicken ovalbumin upstream promoter-transcription factors in the developing mouse central nervous system: evidence for a role in segmental patterning of the diencephalon. Proc Natl Acad Sci USA, 91 (10): 4451-5. [PMID:8183930]
22. Qiu Y, Pereira FA, DeMayo FJ, Lydon JP, Tsai SY, Tsai MJ. (1997) Null mutation of mCOUP-TFI results in defects in morphogenesis of the glossopharyngeal ganglion, axonal projection, and arborization. Genes Dev, 11 (15): 1925-37. [PMID:9271116]
23. Satoh S, Tang K, Iida A, Inoue M, Kodama T, Tsai SY, Tsai MJ, Furuta Y, Watanabe S. (2009) The spatial patterning of mouse cone opsin expression is regulated by bone morphogenetic protein signaling through downstream effector COUP-TF nuclear receptors. J Neurosci, 29 (40): 12401-11. [PMID:19812316]
24. Schaeffer E, Guillou F, Part D, Zakin MM. (1993) A different combination of transcription factors modulates the expression of the human transferrin promoter in liver and Sertoli cells. J Biol Chem, 268 (31): 23399-408. [PMID:8226864]
25. Scott DK, Mitchell JA, Granner DK. (1996) The orphan receptor COUP-TF binds to a third glucocorticoid accessory factor element within the phosphoenolpyruvate carboxykinase gene promoter. J Biol Chem, 271 (50): 31909-14. [PMID:8943235]
26. Shibata H, Nawaz Z, Tsai SY, O'Malley BW, Tsai MJ. (1997) Gene silencing by chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is mediated by transcriptional corepressors, nuclear receptor-corepressor (N-CoR) and silencing mediator for retinoic acid receptor and thyroid hormone receptor (SMRT). Mol Endocrinol, 11 (6): 714-24. [PMID:9171235]
27. Sosa MS, Parikh F, Maia AG, Estrada Y, Bosch A, Bragado P, Ekpin E, George A, Zheng Y, Lam HM et al.. (2015) NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes. Nat Commun, 6: 6170. [PMID:25636082]
28. Sugiyama T, Wang JC, Scott DK, Granner DK. (2000) Transcription activation by the orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI). Definition of the domain involved in the glucocorticoid response of the phosphoenolpyruvate carboxykinase gene. J Biol Chem, 275 (5): 3446-54. [PMID:10652338]
29. Tang K, Xie X, Park JI, Jamrich M, Tsai S, Tsai MJ. (2010) COUP-TFs regulate eye development by controlling factors essential for optic vesicle morphogenesis. Development, 137 (5): 725-34. [PMID:20147377]
30. Tomassy GS, De Leonibus E, Jabaudon D, Lodato S, Alfano C, Mele A, Macklis JD, Studer M. (2010) Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI. Proc Natl Acad Sci USA, 107 (8): 3576-81. [PMID:20133588]
31. Tran P, Zhang XK, Salbert G, Hermann T, Lehmann JM, Pfahl M. (1992) COUP orphan receptors are negative regulators of retinoic acid response pathways. Mol Cell Biol, 12 (10): 4666-76. [PMID:1328857]
32. Wang LH, Tsai SY, Cook RG, Beattie WG, Tsai MJ, O'Malley BW. (1989) COUP transcription factor is a member of the steroid receptor superfamily. Nature, 340 (6229): 163-6. [PMID:2739739]
33. Xie X, Qin J, Lin SH, Tsai SY, Tsai MJ. (2011) Nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) modulates mesenchymal cell commitment and differentiation. Proc Natl Acad Sci USA, 108 (36): 14843-8. [PMID:21873211]
34. Yamaguchi H, Zhou C, Lin SC, Durand B, Tsai SY, Tsai MJ. (2004) The nuclear orphan receptor COUP-TFI is important for differentiation of oligodendrocytes. Dev Biol, 266 (2): 238-51. [PMID:14738874]
35. Zhou C, Qiu Y, Pereira FA, Crair MC, Tsai SY, Tsai MJ. (1999) The nuclear orphan receptor COUP-TFI is required for differentiation of subplate neurons and guidance of thalamocortical axons. Neuron, 24 (4): 847-59. [PMID:10624948]
36. Zhou C, Tsai SY, Tsai MJ. (2001) COUP-TFI: an intrinsic factor for early regionalization of the neocortex. Genes Dev, 15 (16): 2054-9. [PMID:11511537]
37. Zhou X, Liu F, Tian M, Xu Z, Liang Q, Wang C, Li J, Liu Z, Tang K, He M et al.. (2015) Transcription factors COUP-TFI and COUP-TFII are required for the production of granule cells in the mouse olfactory bulb. Development, 142 (9): 1593-605. [PMID:25922524]
