Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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 A₁ into vitamin A₂ to 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 of cyp27c1 but 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 of thrb resulted 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 adult thrb ^-/- retina, of which three (lws1, lws2, and miR-726) occur in a single syntenic cluster. In the thrb ^-/- retina, retinal progenitors destined to become red cones were transfated into ultraviolet (UV) cones and horizontal cells. Taken together, our findings demonstrate cooperative regulation of cyp27c1 by TH receptors and a requirement for thrb in red cone fate determination. Thus, TH signaling coordinately regulates both spectral sensitivity and sensory plasticity.

SUBMITTER: Volkov LI

PROVIDER: S-EPMC7334509 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Insect NMDA receptors mediate juvenile hormone biosynthesis.

Project description:In vertebrates, the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) appears to play a role in neuronal development, synaptic plasticity, memory formation, and pituitary activity. However, functional NMDAR have not yet been characterized in insects. We have now demonstrated immunohistochemically glutamatergic nerve terminals in the corpora allata of an adult female cockroach, Diploptera punctata. Cockroach corpus allatum (CA) cells, exposed to NMDA in vitro, exhibited elevated cytosolic [Ca(2+)], but not in culture medium nominally free of calcium or containing NMDAR-specific channel blockers: MK-801 and Mg(2+). Sensitivity of cockroach corpora allata to NMDA changed cyclically during the ovarian cycle. Highly active glands of 4-day-old mated females, exposed to 3 microM NMDA, produced 70% more juvenile hormone (JH) in vitro, but the relatively inactive glands of 8-day-old mated females showed little response to the agonist. The stimulatory effect of NMDA was eliminated by augmenting the culture medium with MK-801, conantokin, or high Mg(2+). Having obtained substantive evidence of functioning NMDAR in insect corpora allata, we used reverse transcription PCR to demonstrate two mRNA transcripts, DNMDAR1 and DNMDAR2, in the ring gland and brain of last-instar Drosophila melanogaster. Immunohistochemical labeling, using mouse monoclonal antibody against rat NMDAR1, showed that only one of the three types of endocrine cells in the ring gland, CA cells, expressed rat NMDAR1-like immunoreactive protein. This antibody also labeled two brain neurons in the lateral protocerebrum, one neuron per brain hemisphere. Finally, we used the same primers for DNMDAR1 to demonstrate a fragment of putative NMDA receptor in the corpora allata of Diploptera punctata. Our results suggest that the NMDAR has a role in regulating JH synthesis and that ionotropic-subtype glutamate receptors became specialized early in animal evolution.

| S-EPMC117510 | biostudies-literature

Mutant thyroid hormone receptors (TRs) isolated from distinct cancer types display distinct target gene specificities: a unique regulatory repertoire associated with two renal clear cell carcinomas.

Project description:Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that regulate a diverse array of biological activities, including metabolism, homeostasis, and development. TRs also serve as tumor suppressors, and aberrant TR function (via mutation, deletion, or altered expression) is associated with a spectrum of both neoplastic and endocrine diseases. A particularly high frequency of TR mutations has been reported in renal clear cell carcinoma (RCCC) and in hepatocellular carcinoma (HCC). We have shown that HCC-TR mutants regulate only a fraction of the genes targeted by wild-type TRs but have gained the ability to regulate other, unique, targets. We have suggested that this altered gene recognition may contribute to the neoplastic phenotype. Here, to determine the generality of this phenomenon, we examined a distinct set of TR mutants associated with RCCC. We report that two different TR mutants, isolated from independent RCCC tumors, possess greatly expanded target gene specificities that extensively overlap one another, but only minimally overlap that of the wild-type TRs, or those of two HCC-TR mutants. Many of the genes targeted by either or both RCCC-TR mutants have been previously implicated in RCCC and include a series of metallothioneins, solute carriers, and genes involved in glycolysis and energy metabolism. We propose as a hypothesis that TR mutations from RCCC and HCC may play tissue-specific roles in carcinogenesis, and that the divergent target gene recognition patterns of TR mutants isolated from the two different types of tumors may arise from different selective pressures during development of RCCC vs. HCC.

| S-EPMC3146248 | biostudies-literature

Mechanisms of thyroid hormone action.

Project description:Our understanding of thyroid hormone action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a number of cancers. The mechanism of thyroid hormone action has been informed by these clinical observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid hormone transporters, corepressors, and coactivators; thyroid hormone receptor (TR) isoform-specific action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, especially for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function.

| S-EPMC3433956 | biostudies-other

Thyroid hormone receptors in two model species for vertebrate embryonic development: chicken and zebrafish.

Project description:Chicken and zebrafish are two model species regularly used to study the role of thyroid hormones in vertebrate development. Similar to mammals, chickens have one thyroid hormone receptor ? (TR?) and one TR? gene, giving rise to three TR isoforms: TR?, TR?2, and TR?0, the latter with a very short amino-terminal domain. Zebrafish also have one TR? gene, providing two TR?1 variants. The zebrafish TR? gene has been duplicated, and at least three TR? isoforms are expressed: TR?A1-2 and TR?B are very similar, while TR?A1 has a longer carboxy-terminal ligand-binding domain. All these TR isoforms appear to be functional, ligand-binding receptors. As in other vertebrates, the different chicken and zebrafish TR isoforms have a divergent spatiotemporal expression pattern, suggesting that they also have distinct functions. Several isoforms are expressed from the very first stages of embryonic development and early chicken and zebrafish embryos respond to thyroid hormone treatment with changes in gene expression. Future studies in knockdown and mutant animals should allow us to link the different TR isoforms to specific processes in embryonic development.

| S-EPMC3134294 | biostudies-literature

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

Project description: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.

| S-EPMC3751927 | biostudies-literature

Distinct mechanisms mediate visual detection and identification.

Project description:A core organizing principle for studies of the brain is that distinct neural pathways mediate distinct behavioral tasks [1, 2]. When two related tasks are mediated by a common pathway, studies of one are likely to generalize to the other. Here, we test whether performance on two laboratory tasks that model object detection and identification are mediated by common mechanisms of visual adaptation. Although both tasks rely on the luminance pattern in images, their demands on visual processing are quite different. Object detection requires discriminating image luminance differences associated with the light reflected from adjacent objects. To encode these differences reliably, neurons adapt their limited dynamic range to prevailing viewing conditions [3-6]. Object identification, on the other hand, demands a fixed response to light reflected from an object independent of illumination [7]. We compared performance in discrimination and identification tasks for simulated surfaces. In striking contrast to studies with less structured contexts, we found clear evidence that distinct processes mediate judgments in the two tasks. These results challenge models that account for perceived lightness entirely through the action of image-encoding mechanisms.

| S-EPMC2772872 | biostudies-literature

Gaining ligand selectivity in thyroid hormone receptors via entropy.

Project description:Nuclear receptors are important targets for pharmaceuticals, but similarities between family members cause difficulties in obtaining highly selective compounds. Synthetic ligands that are selective for thyroid hormone (TH) receptor beta (TRbeta) vs. TRalpha reduce cholesterol and fat without effects on heart rate; thus, it is important to understand TRbeta-selective binding. Binding of 3 selective ligands (GC-1, KB141, and GC-24) is characterized at the atomic level; preferential binding depends on a nonconserved residue (Asn-331beta) in the TRbeta ligand-binding cavity (LBC), and GC-24 gains extra selectivity from insertion of a bulky side group into an extension of the LBC that only opens up with this ligand. Here we report that the natural TH 3,5,3'-triodothyroacetic acid (Triac) exhibits a previously unrecognized mechanism of TRbeta selectivity. TR x-ray structures reveal better fit of ligand with the TRalpha LBC. The TRbeta LBC, however, expands relative to TRalpha in the presence of Triac (549 A(3) vs. 461 A(3)), and molecular dynamics simulations reveal that water occupies the extra space. Increased solvation compensates for weaker interactions of ligand with TRbeta and permits greater flexibility of the Triac carboxylate group in TRbeta than in TRalpha. We propose that this effect results in lower entropic restraint and decreases free energy of interactions between Triac and TRbeta, explaining subtype-selective binding. Similar effects could potentially be exploited in nuclear receptor drug design.

| S-EPMC2791634 | biostudies-literature

Multiple novel signals mediate thyroid hormone receptor nuclear import and export.

Project description:Thyroid hormone receptor (TR) is a member of the nuclear receptor superfamily that shuttles between the cytosol and nucleus. The fine balance between nuclear import and export of TR has emerged as a critical control point for modulating thyroid hormone-responsive gene expression; however, sequence motifs of TR that mediate shuttling are not fully defined. Here, we characterized multiple signals that direct TR shuttling. Along with the known nuclear localization signal in the hinge domain, we identified a novel nuclear localization signal in the A/B domain of thyroid hormone receptor α1 that is absent in thyroid hormone receptor β1 and inactive in the oncoprotein v-ErbA. Our prior studies showed that thyroid hormone receptor α1 exits the nucleus through two pathways, one dependent on the export factor CRM1 and the other CRM1-independent. Here, we identified three novel CRM1-independent nuclear export signal (NES) motifs in the ligand-binding domain as follows: a highly conserved NES in helix 12 (NES-H12) and two additional NES sequences spanning helix 3 and helix 6, respectively. Mutations predicted to disrupt the α-helical structure resulted in a significant decrease in NES-H12 activity. The high degree of conservation of helix 12 suggests that this region may function as a key NES in other nuclear receptors. Furthermore, our mutagenesis studies on NES-H12 suggest that altered shuttling of thyroid hormone receptor β1 may be a contributing factor in resistance to thyroid hormone syndrome. Taken together, our findings provide a detailed mechanistic understanding of the multiple signals that work together to regulate TR shuttling and transcriptional activity, and they provide important insights into nuclear receptor function in general.

| S-EPMC3438959 | biostudies-literature

Protein Disulfide Isomerase Modulates the Activation of Thyroid Hormone Receptors.

Project description:Thyroid hormone receptors (TRs) are responsible for mediating thyroid hormone (T3 and T4) actions at a cellular level. They belong to the nuclear receptor (NR) superfamily and execute their main functions inside the cell nuclei as hormone-regulated transcription factors. These receptors also exhibit so-called "non-classic" actions, for which other cellular proteins, apart from coregulators inside nuclei, regulate their activity. Aiming to find alternative pathways of TR modulation, we searched for interacting proteins and found that PDIA1 interacts with TR? in a yeast two-hybrid screening assay. The functional implications of PDIA1-TR interactions are still unclear; however, our co-immunoprecipitation (co-IP) and fluorescence assay results showed that PDI was able to bind both TR isoforms in vitro. Moreover, T3 appears to have no important role in these interactions in cellular assays, where PDIA1 was able to regulate transcription of TR? and TR?-mediated genes in different ways depending on the promoter region and on the TR isoform involved. Although PDIA1 appears to act as a coregulator, it binds to a TR surface that does not interfere with coactivator binding. However, the TR:PDIA1 complex affinity and activation are different depending on the TR isoform. Such differences may reflect the structural organization of the PDIA1:TR complex, as shown by models depicting an interaction interface with exposed cysteines from both proteins, suggesting that PDIA1 might modulate TR by its thiol reductase/isomerase activity.

| S-EPMC6331412 | biostudies-literature

Xenopus laevis alpha and beta thyroid hormone receptors.

Project description:The Xenopus laevis genome encodes two genes for the alpha (TR alpha) and two genes for the beta (TR beta) thyroid hormone receptors. The two TR alpha genes closely resemble their rat, human, and chicken counterparts. No alternatively spliced TR alpha cDNA clones were found in the 5' untranslated region (5' UTR). In contrast, complex alternative splicing of TR beta mRNA occurs within the 5' UTR as well as possible alternative transcriptional start sites. As many as eight exons encoding mainly the 5' UTR are alternatively spliced, giving rise to at least two amino termini for each of the two TR beta proteins. The 5' UTR of transcripts from both TR alpha and TR beta genes contain multiple AUG sequences with short open reading frames suggesting translational control mechanisms might play a role in expression of TR genes.

| S-EPMC54689 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data