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Enhancer/promoter activities of the long/middle wavelength-sensitive opsins of vertebrates mediated by thyroid hormone receptor β2 and COUP-TFII.

ABSTRACT: Cone photopigments (opsins) are crucial elements of, and the first detection module in, color vision. Individual opsins have different wavelength sensitivity patterns, and the temporal and spatial expression patterns of opsins are unique and stringently regulated. Long and middle wavelength-sensitive (L/M) opsins are of the same phylogenetic type. Although the roles of thyroid hormone/TRß2 and COUP-TFs in the transcriptional regulation of L/M opsins have been explored, the detailed mechanisms, including the target sequence in the enhancer of L/M opsins, have not been revealed. We aimed to reveal molecular mechanisms of L/M opsins in vertebrates. Using several human red opsin enhancer/promoter-luciferase reporter constructs, we found that TRß2 increased luciferase activities through the 5'-UTR and intron 3-4 region, whereas the presence of T3 affected only the intron 3-4 region-dependent luciferase activity. Furthermore, COUP-TFII suppressed intron 3-4 region-dependent luciferase activities. However, luciferase expression driven by the mouse M opsin intron 3-4 region was only slightly increased by TRß2, and rather enhanced by COUP-TFII. To determine whether these differential responses reflect differences between primates and rodents, we examined the enhancer/promoter region of the red opsin of the common marmoset. Interestingly, while TRß2 increased 5'-UTR- or intron 3-4 region-driven luciferase expression, as observed for the human red opsin, expression of the latter luciferase was not suppressed by COUP-TFII. In fact, immunostaining of common marmoset retinal sections revealed expression of COUP-TFII and red opsin in the cone cells.

SUBMITTER: Iwagawa T

PROVIDER: S-EPMC3751927 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Persistent COUP-TFII expression underlies the myopathy and impaired muscle regeneration observed in resistance to thyroid hormone-alpha.

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COUP-TFII in Health and Disease.

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Thyroid Hormone Distributor Proteins During Development in Vertebrates.

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Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) regulates growth and patterning of the postnatal mouse cerebellum.

Project description:COUP-TFII (also known as Nr2f2), a member of the nuclear orphan receptor superfamily, is expressed in several regions of the central nervous system (CNS), including the ventral thalamus, hypothalamus, midbrain, pons, and spinal cord. To address the function of COUP-TFII in the CNS, we generated conditional COUP-TFII knockout mice using a tissue-specific NSE-Cre recombinase. Ablation of COUP-TFII in the brain resulted in malformation of the lobule VI in the cerebellum and a decrease in differentiation of cerebellar neurons and cerebellar growth. The decrease in cerebellar growth in NSE(Cre/+)/CII(F/F) mice is due to reduced proliferation and increased apoptosis in granule cell precursors (GCPs). Additional studies demonstrated that insulin like growth factor 1 (IGF-1) expression was reduced in the cerebellum of NSE(Cre/+)/CII(F/F) mice, thereby leading to decreased Akt1 and GSK-3beta activities, and the reduced expression of mTOR. Using ChIP assays, we demonstrated that COUP-TFII was recruited to the promoter region of IGF-1 in a Sp1-dependent manner. In addition, dendritic branching of Purkinje cells was decreased in the mutant mice. Thus, our results indicate that COUP-TFII regulates growth and maturation of the mouse postnatal cerebellum through modulation of IGF-1 expression.

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COUP-TFII controls amygdala patterning by regulating neuropilin expression.

Project description:The development of the progenitor zones in the pallium, lateral ganglionic eminence (LGE) and medial ganglionic eminence (MGE) in the subpallium has been well studied; however, so far the role of the caudal ganglionic eminence (CGE), a posterior subpallial domain, in telencephalon patterning remains poorly understood. COUP-TFII, an orphan nuclear receptor, is preferentially expressed in the CGE. We generated COUP-TFII mouse mutants, using Rx-Cre (RxCre;COUP-TFII(F/F)), to study its function in telencephalon development. In these mutants, we found severe defects in the formation of the amygdala complex, including the lateral (LA), basolateral (BLA) and basomedial (BMA) amygdala nuclei. Molecular analysis provided evidence that the migration of CGE-derived Pax6(+) cells failed to settle into the BMA nucleus, owing to reduced expression of neuropilin 1 (Nrp1) and Nrp2, two semaphorin receptors that regulate neuronal cell migration and axon guidance. Our ChIP assays revealed that Nrp1 and Nrp2 genes are the direct targets of COUP-TFII in the telencephalon in vivo. Furthermore, our results showed that the coordinated development between the CGE originated subpallial population (Pax6(+) cells) and pallial populations (Tbr1(+) and Lhx2(+) cells) was essential for patterning the amygdala assembly. Our study presented novel genetic evidence that the caudal ganglionic eminence, a distinct subpallial progenitor zone, contributes cells to the basal telencephalon, such as the BMA nucleus.

| S-EPMC3317968 | biostudies-literature

Thyroid hormone and COUP-TF1 regulate kallikrein-binding protein (KBP) gene expression.

Project description:Kallikrein-binding protein (KBP) is a component of the kallikrein-kinin system that mediates vasodilation and inhibits tumor growth by antagonizing vascular endothelial growth factor-mediated angiogenesis. We demonstrate that KBP gene expression is repressed by T(3) and modulated by the orphan nuclear receptor, chicken ovalbumin upstream promoter transcription factor 1 (COUP-TF1). In hypothyroid mice, KBP mRNA expression in the testis was increased 2.1-fold compared with euthyroid mice. We have identified two negative thyroid hormone response elements (nTREs) in the mouse KBP gene, nTRE1 located in the 5' flanking region (-53 to -29) and nTRE2, located in the first intron (104-132). We used functional assays, cofactor knockdown, and chromatin immunoprecipitation assays to characterize nTRE1 and nTRE2 in hepatic (HepG2) and testes (GC-1spg) cell lines. Reporter expression directed by both elements was enhanced with addition of thyroid hormone receptor and repressed with the addition of T(3). COUP-TF1 enhanced basal expression of both elements but blunted unliganded thyroid hormone receptor enhancement and T(3) repression of nTRE1 but not nTRE2. Both nTREs bound nuclear corepressor and binding increased in response to T(3). Nuclear corepressor knockdown resulted in loss of T(3) repression of both nTRE1 and nTRE2. COUP-TF1, which usually represses T(3) induction of positive thyroid hormone response elements, reverses T(3) repression mediated by nTRE1 in the mouse KBP gene. Endogenous KBP expression is repressed by T(3) and two functional nTREs, both of which are required, have been characterized in the KBP gene. COUP-TF1 may be an important factor to modulate expression of genes that are repressed by T(3).

| S-EPMC3040047 | biostudies-literature

The Nuclear Receptor COUP-TFII Regulates Amhr2 Gene Transcription via a GC-Rich Promoter Element in Mouse Leydig Cells.

Project description:The nuclear receptor chicken ovalbumin upstream promoter-transcription factor type II (COUP-TFII)/NR2F2 is expressed in adult Leydig cells, and conditional deletion of the Coup-tfii/Nr2f2 gene impedes their differentiation. Steroid production is also reduced in COUP-TFII-depleted Leydig cells, supporting an additional role in steroidogenesis for this transcription factor. COUP-TFII action in Leydig cells remains to be fully characterized. In the present work, we report that COUP-TFII is an essential regulator of the gene encoding the anti-Müllerian hormone receptor type 2 (Amhr2), which participates in Leydig cell differentiation and steroidogenesis. We found that Amhr2 mRNA levels are reduced in COUP-TFII-depleted MA-10 Leydig cells. Consistent with this, COUP-TFII directly activates a -1486 bp fragment of the mouse Amhr2 promoter in transient transfection assays. The COUP-TFII responsive region was localized between -67 and -34 bp. Chromatin immunoprecipitation assay confirmed COUP-TFII recruitment to the proximal Amhr2 promoter whereas DNA precipitation assay revealed that COUP-TFII associates with the -67/-34 bp region in vitro. Even though the -67/-34 bp region contains an imperfect nuclear receptor element, COUP-TFII-mediated activation of the Amhr2 promoter requires a GC-rich sequence at -39 bp known to bind the specificity protein (SP)1 transcription factor. COUP-TFII transcriptionally cooperates with SP1 on the Amhr2 promoter. Mutations that altered the GCGGGGCGG sequence at -39 bp abolished COUP-TFII-mediated activation, COUP-TFII/SP1 cooperation, and reduced COUP-TFII binding to the proximal Amhr2 promoter. Our data provide a better understanding of the mechanism of COUP-TFII action in Leydig cells through the identification and regulation of the Amhr2 promoter as a novel target.

| S-EPMC6839530 | biostudies-literature

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