COUP-TFII Research Articles

Hyperactive and anxiolytic-like behaviors result from loss of COUP-TFI/Nr2f1 in the mouse cortex.

The nuclear receptor COUP TFI (also known as Nr2f1) plays major roles in specifying distinct neuronal subtypes during patterning of the neocortical motor and somatosensory cortex, as well as in regulating the longitudinal growth of the hippocampus during development. In humans, mutations in the NR2F1 gene lead to a global developmental delay and intellectual disabilities. While more than 30% of patients show behavioral features of autism spectrum disorder, 16% of haploinsufficient children show signs of hyperactivity and impulsivity. Loss of COUP-TFI in the cortical mouse primordium results in altered area organization and serotonin distribution, abnormal coordination of voluntary movements and learning and memory deficits. Here, we asked whether absence of COUP-TFI affects locomotor activity, anxiety, as well as depression. Mice mutant for COUP-TFI have normal motor coordination, but significant traits of hyperactivity, which does not seem to respond to N-Methyl-D-aspartate (NMDA) antagonists. However, no changes in anxiety, despite increased locomotor performances, were observed in the open field task. On the contrary, elevated plus maze and dark-light test explorations indicate a decreased anxiety-like behavior in COUP-TFI mutant mice. Finally, significantly reduced immobility in the forced swim test and no changes in anhedonia in the sucrose preference task suggest no particular depressive behaviors in mutant mice. Taken together, our study shows that loss of COUP-TFI leads to increased locomotor activity but less anxiety and contributes in further deciphering the pathophysiology of patients haploinsufficient for NR2F1.

Autologous tissue patches acquire vascular identity depending on the environment.

Vascular identity is genetically determined, but can be altered during surgical procedures. We hypothesized that the environment of the procedure critically alters the identity of autologous tissue patches implanted into the arterial or venous environment. Autologous jugular vein or carotid artery was used as a patch to repair a rat aorta or inferior vena cava. In the aortic environment patches contained neointimal cells that were CD34/Ephrin-B2-dual positive but not CD34/Eph-B4-dual positive; patches expressed Ephrin-B2, notch-4 and dll-4 but not Eph-B4 and COUP-TFII. In the venous environment patches contained neointimal cells that were CD34/Eph-B4-dual positive but not CD34/Ephrin-B2-dual positive; patches expressed Eph-B4 and COUP-TFII but not Ephrin-B2, notch-4 and dll-4. These data show that autologous tissue patches heal by acquisition of the vascular identity determined by the environment into which they are implanted, suggesting some plasticity of adult vascular identity.

Regulation roles of COUP transcription factors in the development of embryonic eye

Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) are the orphan receptors of the steroid/thyroid hormone receptor superfamily. These factors include COUP-TFⅠ and COUP-TF Ⅱ, which play critical roles in embryonic development, organogenesis, neurogenesis and cellular differentiation. Many studies showed that COUP-TFs were also involved in the development of embryonic eye. More attention has been paid to the issue that mutations of COUP-TFs genes lead to phenotypes of coloboma, small eyes, optic atrophy, eye retardation, strabismus, and amblyopia. However, the mechanisms of COUP-TFs regulating the development of embryonic eye are not clear. The origin, molecular struture, classification, biological functions, mechanisms of regulating the target genes transcription and development of embryonic eye of COUP-TFs were reviewed. Key words: COUP transcription factorⅠ; COUP transcription factor Ⅱ; Development of embryonic eye; Retinal development

Effects of the COUP-TFI mutation on murine cochlear function

Problem: COUP-TFI (Chicken Ovalbumin Upstream Promoter-Transcription Factor I) is an orphan member of the steroid/thyroid nuclear receptor superfamily. It is highly expressed in the developing nervous system. Null mutant COUP-TFI mice have glossopharyngeal nerve dysfunction that compromises feeding ability and usually results in perinatal death. Surviving null mutant mice demonstrate neuronal differentiation defects, altered thalamocortical axon guidance, and apoptosis of cerebral cortical layer IV. COUP-TFI expression is also important for inner ear organogenesis. Null mutants have a shortened cochlear duct, abnormal cochlear innervation, and malformed vestibular chambers. Additionally, by P20 the organ of Corti in the basal turn has degenerated. Interestingly, the organ of Corti at the mid-modiolar region has only subtle anatomic irregularities and, in particular, contains normal-appearing inner and outer hair cells. We sought to determine the effect of this mutation on cochlear function. Methods: We recorded ABR and DPOAE thresholds in P16-18 null mutant and heterozygote COUP TFI mice, as well as age-matched wild-type controls. ABRs were evoked with a 5 msec sine wave tone pip. DPOAEs were elicited using F2 = 1.2*F1 and L2 = L1. All measurements were performed using stimuli up to 80 dB SPL over the frequency spectrum of 1 to 40 kHz. Results: Null mutant mice had no ABR and no DPOAE responses over the range of stimulation. In contrast, heterozygote and wild-type mice had normal ABR and DPOAE thresholds of 30 to 50 dB in the mid-to-high frequencies. In general, these responses occurred above 6.3 kHz. Conclusion: Both measures of hearing indicate that the COUP-TFI null mutant has profound cochlear dysfunction. Cochlear function in heterozygotes is no different than in wild-type mice. Significance: Even though these mutants have cochleae with many normal anatomic features, these features do not appear to have physiologic relevance. These mutants may be a good model of congenital hearing loss associated with otic capsule malformation. Support: None reported.

Expression Profiles of COUP–TF, DAX-1, and SF-1 in the Human Adrenal Gland and Adrenocortical Tumors: Possible Implications in Steroidogenesis

Chicken ovalbumin upstream promoter–transcription factor (COUP–TF), DAX-1, and steroidogenic factor-1 (SF-1) are orphan members of the nuclear hormone receptor superfamily. COUP–TF and DAX-1 have been shown to negatively regulate the transcriptional activity of SF-1, a steroidogenic cell-specific activator of various steroidogenic cytochrome P450 genes. We therefore examined the expression levels and immunolocalization of COUP–TF, DAX-1, and SF-1 in human adrenal gland (NL) and adrenocortical adenomas, and compared the results with CYP17 expression levels and its enzyme activities to study their potential correlation with adrenocortical steroidogenesis. In NL (n = 10), expressions of COUP–TF, DAX-1, and SF-1 were detected in the nuclei of adrenocortical cells, but not in the medulla. In cortisol-producing adenomas causing Cushing syndrome (CS, n = 20), CYP17 expression was upregulated (298 ± 2% vs NL 98 ± 4%), whereas expression levels of both COUP–TFs (COUP–TFI, 52 ± 5% vs NL 98 ± 4%; COUP–TFII, 18 ± 4% vs NL 98 ± 4%) and DAX-1 (42 ± 4% vs NL 100 ± 4%) were reduced. In deoxycorticosterone-producing adenomas (DOC, n = 2), on the other hand, CYP17 expression was extremely reduced (8 and 12% vs NL 98 ± 4%), whereas DAX-1 expression increased markedly (350 and 360% vs NL 100 ± 4%). Expression levels of SF-1 did not differ between NL (100 ± 8%) and CS (106 ± 10%), but its expression appeared to be decreased in DOC (25 and 20%). These results showed CYP17 expression to be upregulated and downregulated in CS and DOC, respectively, in a manner reciprocal to that of its repressors, COUP–TF and/or DAX-1. In summary, the results indicate that co-localization of COUP–TF, DAX-1, and SF-1 in NL was lost in adrenocortical tumors and that these orphan receptors play an important role in the regulation of steroidogenesis in human adrenals.

Functional study of the E276Q mutant hepatocyte nuclear factor-4alpha found in type 1 maturity-onset diabetes of the young: impaired synergy with chicken ovalbumin upstream promoter transcription factor II on the hepatocyte nuclear factor-1 promoter.

Seven mutations in the hepatocyte nuclear factor (HNF)-4alpha gene have been shown to correlate with type 1 maturity-onset diabetes of the young (MODY 1), a monogenic form of type 2 diabetes. Up to now, only the functional properties of two MODY 1 HNF-4alpha mutants, Q268X and V393I, have been investigated to address how the mutations in the HNF-4alpha gene, found by genetic studies, can give rise to impaired activities of mutated HNF-4alpha proteins and can cause this disease. The E276Q mutation results in a nonconservative substitution occurring in the HNF-4alpha E domain, which is involved in dimerization and transactivation activities as well as in protein-protein interactions with other transcription factors or coactivators. Using the mutated human HNF-4alpha2, we have found that, in the absence of chicken ovalbumin upstream promoter transcription factor II (COUP TFII), the E276Q substitution does not significantly affect the dimerization and transactivating activities of HNF-4alpha, at least on the promoters studied herein. On the other hand, in the presence of COUP TFII, the substitution impairs the enhancement of HNF-4-mediated activation of HNF-1 promoter. The impaired synergy between COUP TFII and HNF-4 on the HNF-1 promoter results from an alteration of their interaction. HNF-1 expression plays a crucial role in transactivation of insulin promoter and of numerous genes coding for enzymes involved in glucose homeostasis. Therefore, its downregulation resulting from the E276Q mutation in HNF-4alpha gene most probably impairs the function of pancreatic beta-cells.