scholarly journals Thyroid hormone receptors mediate two distinct mechanisms of long-wavelength vision

2020 ◽  
Vol 117 (26) ◽  
pp. 15262-15269 ◽  
Author(s):  
Leo I. Volkov ◽  
Jeong Sook Kim-Han ◽  
Lauren M. Saunders ◽  
Deepak Poria ◽  
Andrew E. O. Hughes ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Vitamin A ◽  
Nuclear Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Retinal Pigment ◽  
Cytochrome P450 Enzyme ◽  
Sequencing Analysis ◽  
Long Wavelength ◽  
Sensory Plasticity

Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina,thyroid hormone receptor β(thrb) is required for expression of long-wavelength-sensitive opsin (lws) in red cone photoreceptors, while in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme,cyp27c1, that converts vitamin A1into vitamin A2to produce a red-shifted chromophore. To better understand how TH controls these processes, we analyzed the phenotype of zebrafish with mutations in the three known TH nuclear receptor transcription factors (thraa,thrab,and thrb). We found that no single TH nuclear receptor is required for TH-mediated induction ofcyp27c1but that deletion of all three (thraa−/−;thrab−/−;thrb−/−) completely abrogates its induction and the resulting conversion of A1- to A2-based retinoids. In the retina, loss ofthrbresulted in an absence of red cones at both larval and adult stages without disruption of the underlying cone mosaic. RNA-sequencing analysis revealed significant down-regulation of only five genes in adultthrb−/−retina, of which three (lws1,lws2, andmiR-726) occur in a single syntenic cluster. In thethrb−/−retina, retinal progenitors destined to become red cones were transfated into ultraviolet (UV) cones and horizontal cells. Taken together, our findings demonstrate cooperative regulation ofcyp27c1by TH receptors and a requirement forthrbin red cone fate determination. Thus, TH signaling coordinately regulates both spectral sensitivity and sensory plasticity.

scholarly journals Nuclear Receptor Corepressor Recruitment by Unliganded Thyroid Hormone Receptor in Gene Repression during Xenopus laevis Development

2002 ◽  
Vol 22 (24) ◽  
pp. 8527-8538 ◽  
Author(s):  
Laurent M. Sachs ◽  
Peter L. Jones ◽  
Emmanuelle Havis ◽  
Nicole Rouse ◽  
Barbara A. Demeneix ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Xenopus Laevis ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Gene Repression ◽  
Nuclear Receptor Corepressor

ABSTRACT Thyroid hormone receptors (TR) act as activators of transcription in the presence of the thyroid hormone (T3) and as repressors in its absence. While many in vitro approaches have been used to study the molecular mechanisms of TR action, their physiological relevance has not been addressed. Here we investigate how TR regulates gene expression during vertebrate postembryonic development by using T3-dependent amphibian metamorphosis as a model. Earlier studies suggest that TR acts as a repressor during premetamorphosis when T3 is absent. We hypothesize that corepressor complexes containing the nuclear receptor corepressor (N-CoR) are key factors in this TR-dependent gene repression, which is important for premetamorphic tadpole growth. To test this hypothesis, we isolated Xenopus laevis N-CoR (xN-CoR) and showed that it was present in pre- and metamorphic tadpoles. Using a chromatin immunoprecipitation assay, we demonstrated that xN-CoR was recruited to the promoters of T3 response genes during premetamorphosis and released upon T3 treatment, accompanied by a local increase in histone acetylation. Furthermore, overexpression of a dominant-negative N-CoR in tadpole tail muscle led to increased transcription from a T3-dependent promoter. Our data indicate that N-CoR is recruited by unliganded TR to repress target gene expression during premetamorphic animal growth, an important process that prepares the tadpole for metamorphosis.

The functional relationship between co-repressor N-CoR and SMRT in mediating transcriptional repression by thyroid hormone receptor α

2008 ◽  
Vol 411 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Kyung-Chul Choi ◽  
So-Young Oh ◽  
Hee-Bum Kang ◽  
Yoo-Hyun Lee ◽  
Seungjoo Haam ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Transcriptional Repression ◽  
Fatty Acid Synthase ◽  
Hormone Receptors ◽  
Target Genes ◽  
Functional Relationship ◽  
Thyroid Hormone Receptor ◽  
B Cell Lymphoma ◽  
Hormone Response Elements

A central issue in mediating repression by nuclear hormone receptors is the distinct or redundant function between co-repressors N-CoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor). To address the functional relationship between SMRT and N-CoR in TR (thyroid hormone receptor)-mediated repression, we have identified multiple TR target genes, including BCL3 (B-cell lymphoma 3-encoded protein), Spot14 (thyroid hormone-inducible hepatic protein), FAS (fatty acid synthase), and ADRB2 (β-adrenergic receptor 2). We demonstrated that siRNA (small interfering RNA) treatment against either N-CoR or SMRT is sufficient for the de-repression of multiple TR target genes. By the combination of sequence mining and physical association as determined by ChIP (chromatin immunoprecipitation) assays, we mapped the putative TREs (thyroid hormone response elements) in BCL3, Spot14, FAS and ADRB2 genes. Our data clearly show that SMRT and N-CoR are independently recruited to various TR target genes. We also present evidence that overexpression of N-CoR can restore repression of endogenous genes after knocking down SMRT. Finally, unliganded, co-repressor-free TR is defective in repression and interacts with a co-activator, p300. Collectively, these results suggest that both SMRT and N-CoR are limited in cells and that knocking down either of them results in co-repressor-free TR and consequently de-repression of TR target genes.

scholarly journals The thyroid hormone receptor gene (c-erbA alpha) is expressed in advance of thyroid gland maturation during the early embryonic development of Xenopus laevis.

1991 ◽  
Vol 11 (10) ◽  
pp. 5079-5089 ◽  
Author(s):  
D E Banker ◽  
J Bigler ◽  
R N Eisenman
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Xenopus Laevis ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Thyroid Hormone Receptors ◽  
Stages Of Development ◽  
Xenopus Development

The c-erbA proto-oncogene encodes the thyroid hormone receptor, a ligand-dependent transcription factor which plays an important role in vertebrate growth and development. To define the role of the thyroid hormone receptor in developmental processes, we have begun studying c-erbA gene expression during the ontogeny of Xenopus laevis, an organism in which thyroid hormone has well-documented effects on morphogenesis. Using polymerase chain reactions (PCR) as a sensitive assay of specific gene expression, we found that polyadenylated erbA alpha RNA is present in Xenopus cells at early developmental stages, including the fertilized egg, blastula, gastrula, and neurula. By performing erbA alpha-specific PCR on reverse-transcribed RNAs from high-density sucrose gradient fractions prepared from early-stage embryos, we have demonstrated that these erbA transcripts are recruited to polysomes. Therefore, erbA is expressed in Xenopus development prior to the appearance of the thyroid gland anlage in tailbud-stage embryos. This implies that erbA alpha/thyroid hormone receptors may play ligand-independent roles during the early development of X. laevis. Quantitative PCR revealed a greater than 25-fold range in the steady-state levels of polyadenylated erbA alpha RNA across early stages of development, as expressed relative to equimolar amounts of total embryonic RNA. Substantial increases in the levels of erbA alpha RNA were noted at stages well after the onset of zygotic transcription at the mid-blastula transition, with accumulation of erbA alpha transcripts reaching a relative maximum in advance of metamorphosis. We also show that erbA alpha RNAs are expressed unequally across Xenopus neural tube embryos. This differential expression continues through later stages of development, including metamorphosis. This finding suggests that erbA alpha/thyroid hormone receptors may play roles in tissue-specific processes across all of Xenopus development.

Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles

2000 ◽  
Vol 278 (6) ◽  
pp. R1545-R1554 ◽  
Author(s):  
Fushun Yu ◽  
Sten Göthe ◽  
Lilian Wikström ◽  
Douglas Forrest ◽  
Björn Vennström ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Receptor Gene ◽  
Type I ◽  
Variable Response ◽  
Slow Type ◽  
Isoform Expression ◽  
Edl Muscle ◽  
Deficient Mice

Skeletal muscle is known to be a target for the active metabolite of thyroid hormone, i.e., 3,5,3′-triiodothyronine (T3). T3 acts by repressing or activating genes coding for different myosin heavy chain (MHC) isoforms via T3 receptors (TRs). The diverse function of T3 is presumed to be mediated by TR-α1 and TR-β, but the function of specific TRs in regulating MHC isoform expression has remained undefined. In this study, TR-deficient mice were used to expand our knowledge of the mechanisms by which T3 regulates the expression of specific MHC isoforms via distinct TRs. In fast-twitch extensor digitorum longus (EDL) muscle, TR-α1-, TR-β-, or TR-α1β-deficient mice showed a small but statistically significant decrease ( P < 0.05) of type IIB MHC content and an increased number of type I fibers. In the slow-twitch soleus, the β/slow MHC (type I) isoform was significantly ( P < 0.001) upregulated in the TR-deficient mice, but this effect was highly dependent on the type of receptor deleted. The lack of TR-β had no significant effect on the expression of MHC isoforms. An increase ( P < 0.05) of type I MHC was observed in the TR-α1-deficient muscle. A dramatic overexpression ( P < 0.001) of the slow type I MHC and a corresponding downregulation of the fast type IIA MHC ( P < 0.001) was observed in TR-α1β-deficient mice. The muscle- and fiber-specific differences in MHC isoform expression in the TR-α1β-deficient mice resembled the MHC isoform transitions reported in hypothyroid animals, i.e., a mild MHC transition in the EDL, a dramatic but not complete upregulation of the β/slow MHC isoform in the soleus, and a variable response to TR deficiency in different soleus muscle fibers. Thus the consequences on muscle are similar in the absence of thyroid hormone or absence of thyroid hormone receptors, indicating that TR-α1 and TR-β together mediate the known actions of T3. However, it remains unknown how thyroid hormone exerts muscle- and muscle fiber-specific effects in its action. Finally, although developmental MHC transitions were not studied specifically in this study, the absence of embryonic and fetal MHC isoforms in the TR-deficient mice indicates that ultimately the transition to the adult MHC isoforms is not solely mediated by TRs.

The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms

1993 ◽  
Vol 13 (10) ◽  
pp. 5970-5980
Author(s):  
H W Chen ◽  
M L Privalsky
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Nuclear Hormone Receptors ◽  
Dominant Negative Inhibitor ◽  
Dominant Negative Mutations ◽  
Microbial Systems ◽  
Dna Binding Properties ◽  
Activate Gene

Genetic lesions that function as dominant negative mutations in microbial systems have long been recognized. It is only relatively recently, however, that similar dominant negative mutations have been implicated as a basis for genetic and neoplastic disorders in vertebrates. We describe here a dissection of the actions of the erbA oncogene protein, an aberrant form of thyroid hormone receptor that acts as a dominant negative inhibitor of other nuclear hormone receptors. We demonstrate that the ErbA oncoprotein interferes with thyroid hormone and trans-retinoic acid receptors by competing for binding to the corresponding response elements. Heterodimerization of the ErbA oncoprotein with these receptors does not play an observable role in repression. In contrast, however, the ErbA oncoprotein does efficiently form a heterodimer with the retinoid X receptor (RXR) class of nuclear hormone receptors; complex formation enhances the DNA-binding properties of the ErbA protein but dramatically interferes with the ability of the RXR component to activate gene expression. Our results indicate that the erbA oncogene may play a previously unanticipated role in neoplasia by interfering with RXR function.

scholarly journals A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily.

1994 ◽  
Vol 14 (10) ◽  
pp. 7025-7035 ◽  
Author(s):  
R Apfel ◽  
D Benbrook ◽  
E Lernhardt ◽  
M A Ortiz ◽  
G Salbert ◽  
...  
Keyword(s):  
Amino Acid ◽  
Thyroid Hormone ◽  
Dna Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Dna Sequences ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Orphan Receptor ◽  
Retinoid Receptor

The steroid/hormone nuclear receptor superfamily comprises several subfamilies of receptors that interact with overlapping DNA sequences and/or related ligands. The thyroid/retinoid hormone receptor subfamily has recently attracted much interest because of the complex network of its receptor interactions. The retinoid X receptors (RXRs), for instance, play a very central role in this subfamily, forming heterodimers with several receptors. Here we describe a novel member of this subfamily that interacts with RXR. Using a v-erbA probe, we obtained a cDNA which encodes a novel 445-amino-acid protein, RLD-1, that contains the characteristic domains of nuclear receptors. Northern (RNA) blot analysis showed that in mature rats, the receptor is highly expressed in spleen, pituitary, lung, liver, and fat. In addition, weaker expression is observed in several other tissues. Amino acid sequence alignment and DNA-binding data revealed that the DNA-binding domain of the new receptor is related to that of the thyroid/retinoid subgroup of nuclear receptors. RLD-1 preferentially binds as a heterodimer with RXR to a direct repeat of the half-site sequence 5'-G/AGGTCA-3', separated by four nucleotides (DR-4). Surprisingly, this binding is dependent to a high degree on the nature of the spacing nucleotides. None of the known nuclear receptor ligands activated RLD-1. In contrast, a DR-4-dependent constitutive transcriptional activation of a chloramphenicol acetyltransferase reporter gene by the RLD-1/RXR alpha heterodimer was observed. Our data suggest a highly specific role for this novel receptor within the network of gene regulation by the thyroid/retinoid receptor subfamily.

scholarly journals Expression of thyroid hormone receptors A and B in developing rat tissues; evidence for extensive posttranscriptional regulation

2007 ◽  
Vol 38 (5) ◽  
pp. 523-535 ◽  
Author(s):  
Richard Keijzer ◽  
Piet-Jan E Blommaart ◽  
Wil T Labruyère ◽  
Jacqueline L M Vermeulen ◽  
Behrouz Zandieh Doulabi ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Expression Pattern ◽  
Posttranscriptional Regulation ◽  
Time Course ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Tissue Expression ◽  
Translational Efficiency ◽  
Rat Tissues ◽  
High Turnover

The perinatal changes in the pattern of expression of the thyroid hormone receptor (TR) isoforms TRα 1 TRα 2, TRβ 1, and TRβ 2 were investigated using in situ hybridization and immunohistochemistry, and RT-PCR and western blotting as visualization and quantification techniques respectively. In liver, lung, and kidney, TRα mRNA was expressed in the stromal and TRβ mRNA in the parenchymal component of the tissues. When compared with liver, TRα mRNA concentrations were tenfold higher in lung, kidney, and intestine, and 100-fold higher in brain, with TRα 2 mRNA concentrations exceeding those of TRα 1 5-to 10-fold. Tissue TRβ 1 mRNA concentrations were similar in liver, lung, and brain, and 3- to 5-fold higher in kidney and intestine. None of the TRβ 2 mRNA could be detected outside the pituitary. Tissue TRα 2 and TRβ 1 protein levels reached adult levels at 5 days before birth, whereas TRα 1 protein peaked after birth. Because of the distinct time-course of thyroid hormone-binding receptors TRα 1 and TRβ 1, we speculate that an initiating, TRβ 1-mediated signaling from the parenchyma is followed by a TRα 1-mediated response in the stroma. When compared with organs with a complementary parenchymal–stromal expression pattern, organs with extensive cellular co-expression of TRα and TRβ (brain and intestinal epithelium) were characterized by a very low TRα protein: mRNA ratio, implying a low translational efficiency of TR mRNA or a high turnover of TR protein. The data indicate that the TR-dependent regulatory cascades are controlled differently in organs with a complementary tissue expression pattern and in those with cellular co-expression of the TRα and TRβ genes.

scholarly journals Inhibition of Estrogen Receptor Action by the Orphan Receptor SHP (Short Heterodimer Partner)

1998 ◽  
Vol 12 (10) ◽  
pp. 1551-1557 ◽  
Author(s):  
Wongi Seol ◽  
Bettina Hanstein ◽  
Myles Brown ◽  
David D. Moore
Keyword(s):  
Estrogen Receptor ◽  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Orphan Receptor ◽  
Estrogen Signaling ◽  
Dependent Manner ◽  
Interaction Domain ◽  
Short Heterodimer Partner

Abstract SHP (short heterodimer partner) is an unusual orphan receptor that lacks a conventional DNA-binding domain. Previous results have shown that it interacts with several other nuclear hormone receptors, including the retinoid and thyroid hormone receptors, and inhibits their ligand-dependent transcriptional activation. Here we show that SHP also interacts with estrogen receptors and inhibits their function. In mammalian and yeast two-hybrid systems as well as glutathione-S-transferase pull-down assays, SHP interacts specifically with estrogen receptor-α (ERα) in an agonist-dependent manner. The same assay systems using various deletion mutants of SHP map the interaction domain with ERα to the same SHP sequences required for interaction with the nonsteroid hormone receptors such as retinoid X receptor and thyroid hormone receptor. In transient cotransfection assays, SHP inhibits estradiol -dependent activation by ERα by about 5-fold. In contrast, SHP interacts with ERβ independent of ligand and reduces its ability to activate transcription by only 50%. These data suggest that SHP functions to regulate estrogen signaling through a direct interaction with ERα.

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