Disease relevance of Nr2f2

• Coup-TFII is up-regulated in adenovirus type 12 tumorigenic cells and is a repressor of MHC class I transcription [1].
• Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia [2].
• COUP-TFII +/- females show significantly reduced fecundity, irregular estrus cycles, delayed puberty, and retarded postnatal growth [3].
• Here, we show that mouse embryos compound mutant for Foxc1 and Foxc2, two closely related Fox transcription factors, exhibit arteriovenous malformations and lack of induction of arterial markers whereas venous markers such as COUP-TFII are normally expressed, suggesting that mutant endothelial cells fail to acquire an arterial fate [4].

High impact information on Nr2f2

• Mediation of Sonic hedgehog-induced expression of COUP-TFII by a protein phosphatase [5].
• In fact, the expression of Angiopoietin-1, a proangiogenic soluble factor thought to mediate the mesenchymal-endothelial interactions during heart development and vascular remodeling, is down-regulated in COUP-TFII mutants [6].
• This down-regulation suggests that COUP-TFII may be required for bidirectional signaling between the endothelial and mesenchymal compartments essential for proper angiogenesis and heart development [6].
• The embryonic expression of COUP-TFII, an orphan nuclear receptor, suggests that it may participate in mesenchymal-epithelial interactions required for organogenesis [6].
• One of these, COUP-TF II, is expressed in embryonic/fetal erythroid cell lines, murine yolk sac, intra-embryonic splanchnopleura and fetal liver [7].

Biological context of Nr2f2

• Nevertheless, further airway branching appears to require downregulation of RA pathways by decreased synthesis, increased RA degradation in the epithelium via P450RAI-mediated metabolism, and inhibition of RA signaling in the mesenchyme by COUPTF-II expression [8].
• COUP-TF2-null embryos die during embryonic development with defective angiogenesis and cardiac defects, a pattern that partly resembles the FOG-2-null phenotype [9].
• Transfection of increasing amounts of the ARP-1 expression vector blocks the PPAR alpha/RXR alpha-mediated induction of transcription from the CYP4A6 promoter [10].
• A similar sequence found in the promoter region of the rat CYP4A1 gene does not, however, bind either PPAR alpha/RXR alpha or ARP-1 [10].
• Electrophoretic mobility shift assays performed with COUP-TF II antibody to examine its interaction with a labeled peroxisome proliferator response element probe showed enhanced binding of COUP-TFII in cardiac nuclear extracts from troglitazone-treated mice for 10 days but not in the control nuclear extracts [11].

Anatomical context of Nr2f2

• The interaction between COUP-TF2 and FOG-2 in mammalian cells was confirmed by co-immunoprecipitation of these proteins from transfected COS-7 cells [9].
• In the adult mouse kidney, COUP-TFII is detected in distal tubules, podocytes, and the epithelial cells of the Bowman's capsule [12].
• The proximal part of the S-shaped body that will become the glomerulus after endothelial cell migration shows COUP-TFII expression in podocyte precursor cells and epithelial cells of the Bowman's capsule [12].
• However, COUP-TF1 and ARP-1 were found to be expressed predominantly in the developing central nervous system in mutually exclusive domains [13].
• We found that COUP-TFII mRNA and protein were present in fetal and adult hepatocytes [14].

Associations of Nr2f2 with chemical compounds

• We have isolated the murine homologs of the members of the COUP-family of steroid hormone receptors, COUP-TF1, ARP-1 and EAR2 [13].
• Overall, the findings presented here show that 10 days of troglitazone treatment decreased expression of the ACO gene through a mechanism involving the transcriptional repressor COUP-TF II [11].
• Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) has been implicated in the control of blood glucose by its potent effect on expression and signaling of various nuclear receptors [15].
• The element RE3 which is the major retinoic acid (RA) response element also binds the transcription factors HNF-4 and ARP-1 [16].
• COUP-TF II diminished the homodimeric binding of the thyroid hormone receptor and the heterodimeric binding of thyroid hormone and retinoid X receptor complexes to these TREs [17].

Physical interactions of Nr2f2

• The inhibition of MyoD-mediated trans-activation involves the direct binding of the DNA binding domain/C-region and hinge/D-regions [i.e. amino acid (aa) residues 78-213] of COUP-TF II to the N-terminal activation domain of MyoD [18].

Regulatory relationships of Nr2f2

• Thus, COUP-TFII has a critical role in repressing Notch signalling to maintain vein identity, which suggests that vein identity is under genetic control and is not derived by a default pathway [19].
• However, this enhancer-bound NF-kappaB failed to up-regulate class I expression because the class I enhancer chromatin remained repressed as a result of histone deacetylation by HDAC in association with COUP-TFII [20].

Other interactions of Nr2f2

• Full-length FOG-2 markedly enhanced transcriptional repression by GAL4-COUP-TF2(117-414), but not by a COUP-TF2 repression domain mutant [9].
• The expression patterns of COUP-TF1, ARP-1 and EAR2 during development were investigated by in situ hybridization [13].
• These results indicate that the PPREs of the CYP4A6 gene are recognized by multiple members of the nuclear receptor family that are likely to contribute to the regulation of CYP4A6 expression in both an agonistic (RXR alpha) and an antagonistic (ARP-1) manner [10].
• Finally, COUP-TFII expression was detected in pancreas, as judged by co-expression of the beta-gal in some of the glucagon and PDX1 positive-cells at 12.5 dpc and co-expression with insulin positive-cells at 15.5 dpc [14].
• Significantly, NF-kappaB p50/p52 double-knockout cells enabled us to demonstrate directly that COUP-TFII can completely repress both nonactivated and NF-kappaB-activated MHC class I transcription [1].

Analytical, diagnostic and therapeutic context of Nr2f2

• Next, with the help of transplantations and gain-of-function studies in organotypic cultures, we have shown that COUP-TFI and COUP-TFII are expressed in distinct and non-overlapping migratory routes [21].
• Using organ cultures and cyclopamine treatment, we showed downregulation of COUP-TFII level in the stomach, suggesting COUP-TFII as a target of hedgehog signaling in the stomach [22].
• COUP-TF II mRNA levels were increased in the spinal cord VZ after treatment, while in the telencephalon, IZ mRNA levels were decreased in the E11 embryos and increased in E13 embryos [23].

References