Thyroid Hormone Receptor Gene Expression Research Articles

Thyroid hormone receptor: A new player in epinephrine-induced larval metamorphosis of the hard-shelled mussel

Many marine invertebrate larvae undergo a dramatic morphological and physiological transition from a planktonic larva to a benthic juvenile. The mechanisms of this metamorphosis in bivalves are mainly unknown. The recent identification in bivalves of a thyroid hormone receptor (TR) gene raises the possibility that as occurs in vertebrate metamorphosis, TRs regulate this developmental process. An evolutionary study of TR receptors revealed they are ubiquitous in the molluscs. Knock-down of the TR gene in pediveliger larvae of the hard-shelled mussel, Mytilus coruscus (Mc), using electroporation of siRNA significantly (p < 0.01) reduced TR gene expression. TR gene knock-down decreased pediveliger larval metamorphosis by 54% and was associated with a significant (p < 0.01) reduction in viability compared to control larvae. The TR in the hard-shelled mussel appears to be an essential regulatory factor for the successful epinephrine-induced metamorphosis of the pediveliger larvae to post-larvae. It is hypothesised that the knock-down of TR by siRNA transfection affects the “competence” of pediveliger larvae for the metamorphic transition by reducing their ability to respond to the inducer. The involvement of TR in the epinephrine-induced metamorphosis of a mollusc, the hard-shelled mussel, suggests the role of TR in this process probably emerged early during evolution.

Evaluation of the effect of acetochlor on thyroid hormone receptor gene expression in the brain and behavior of Rana catesbeiana tadpoles

The thyroid hormones (THs) including 3,5,3′-triiodothyronine (T 3), are important regulators of growth and development of the brain in vertebrates. Previous studies showed that acetochlor, a widely used herbicide, accelerates T 3-induced frog tadpole metamorphosis and elevates the T 3-dependent accumulation of the mRNAs encoding the TH receptors, TRα and β, in the tail. Here we show that acetochlor affects the expression of these TR isoforms in the brain of Rana catesbeiana tadpoles. Premetamorphic tadpoles exposed to 10 nM acetochlor with and without 100 nM T 3 for 4 days showed substantial increases in TRα and TRβ transcript levels and significant decreases in the TRα/TRβ ratios in their brains. This change in TR ratios is recapitulated with 10 nM acetochlor in R. catesbeiana tadpole brains during prometamorphosis, a period in which THs are endogenously produced. Tail fin biopsies revealed an elevation in TRα and β mRNA levels compared to control animals when exposed to 1 and 10 nM acetochlor for 6 days. When subsequently reared in clean water for 59 days, no alterations in metamorphic hallmarks (forelimb emergence, mouth development, tail regression) were noted compared to the controls. Since alterations in TR ratios/levels may impact brain development, we tested the escape behavior in premetamorphic tadpoles exposed to 10 nM acetochlor for 4 days. We did not detect any statistically significant differences that would indicate that acetochlor affects escape behavior. However, since the gene expression data suggest that brain function may be affected, additional studies examining different behaviors upon acetochlor exposure at environmentally-relevant concentrations are warranted.

PCB-Related Alteration of Thyroid Hormones and Thyroid Hormone ReceptorGene Expression in Free-Ranging Harbor Seals ( Phoca vitulina )

Persistent organic pollutants are environmental contaminants that, because of their lipophilic properties and long half-lives, bioaccumulate within aquatic food webs and often reach high concentrations in marine mammals, such as harbor seals (Phoca vitulina). Exposure to these contaminants has been associated with developmental abnormalities, immunotoxicity, and reproductive impairment in marine mammals and other high-trophic-level wildlife, mediated via a disruption of endocrine processes. The highly conserved thyroid hormones (THs) represent one vulnerable endocrine end point that is critical for metabolism, growth, and development in vertebrates. We characterized the relationship between contaminants and specific TH receptor (TR ) gene expression in skin/blubber biopsy samples, as well as serum THs, from free-ranging harbor seal pups (n = 39) in British Columbia, Canada, and Washington State, USA. We observed a contaminant-related increase in blubber TR-α gene expression [total polychlorinated biphenyls (∑PCBs); r = 0.679; p < 0.001] and a concomitant decrease in circulating total thyroxine concentrations (∑PCBs; r = −0.711; p < 0.001). Consistent with results observed in carefully controlled laboratory and captive feeding studies, our findings suggest that the TH system in harbor seals is highly sensitive to disruption by environmental contaminants. Such a disruption not only may lead to adverse effects on growth and development but also could have important ramifications for lipid metabolism and energetics in marine mammals.

Region-specific effects of hypothyroidism on the relative expression of thyroid hormone receptors in adult rat brain

The aim of this study was to determine whether changes in the circulating thyroid hormone (TH) and brain synaptosomal TH content affected the relative levels of mRNA encoding different thyroid hormone receptor (TR) isoforms in adult rat brain. Northern analysis of polyA+RNA from cerebral cortex, hippocampus and cerebellum of control and hypothyroid adult rats was performed in order to determine the relative expression of all TR isoforms. Circulating and synaptosomal TH concentrations were determined by radioimmunoassay. Region-specific quantitative differences in the expression pattern of all TR isoforms in euthyroid animals and hypothyroid animals were recorded. In hypothyroidism, the levels of TRalpha2 mRNA (non-T3-binding isoform) were decreased in all brain regions examined. In contrast the relative expression of TRalpha1 was increased in cerebral cortex and hippocampus, whereas in cerebellum remained unaffected. The TRbeta1 relative expression in cerebral cortex and hippocampus of hypothyroid animals was not affected, whereas this TR isoform was not detectable in cerebellum. The TR isoform mRNA levels returned to control values following T4 intraperitoneal administration to the hypothyroid rats. The obtained results show that in vivo depletion of TH regulates TR gene expression in adult rat brain in a region-specific manner.

Thyroid Hormone Receptor Gene Expression in First Trimester Human Fetal Brain

Maternal thyroid hormone is transferred to the fetus early in pregnancy and is postulated to regulate brain development. Thyroid hormone nuclear receptor (TR) proteins are present in fetal brain, but their isoformal composition is unknown. We therefore investigated the ontogeny of TR isoforms and related splice variants in first trimester human fetal brain (n = 9) by semi-quantitative reverse transcriptase-polymerase chain reaction analysis. Expression of the TRβ1, TRα1 and c-erbAα2 isoforms was detected from 8.1 weeks gestation (wg). An additional truncated species was detected with the c-erbAα2 primer set, consistent with the c-erbAα3 splice variant previously described in the rat. All c-erbAα-derived transcripts were co-ordinately expressed and increased (ca.8-fold) between 8.1 and 13.9 wg. A more complex ontogenic pattern was observed for TRβ1, suggestive of a nadir between 8.4 and 12.0 wg. These findings point to an important role for the TRα1 isoform in mediating maternal thyroid hormone action during first trimester human fetal brain development.

Thyroid hormone receptor gene expression in first trimester human fetal brain.

Maternal thyroid hormone is transferred to the fetus early in pregnancy and is postulated to regulate brain development. Thyroid hormone nuclear receptor (TR) proteins are present in fetal brain, but their isoformal composition is unknown. We therefore investigated the ontogeny of TR isoforms and related splice variants in first trimester human fetal brain (n = 9) by semi-quantitative reverse transcriptase-polymerase chain reaction analysis. Expression of the TRbeta1, TRalpha1 and c-erbAalpha2 isoforms was detected from 8.1 weeks gestation (wg). An additional truncated species was detected with the c-erbAalpha2 primer set, consistent with the c-erbAalpha3 splice variant previously described in the rat. All c-erbAalpha-derived transcripts were co-ordinately expressed and increased (ca. 8-fold) between 8.1 and 13.9 wg. A more complex ontogenic pattern was observed for TRbeta1, suggestive of a nadir between 8.4 and 12.0 wg. These findings point to an important role for the TRalpha1 isoform in mediating maternal thyroid hormone action during first trimester human fetal brain development.

Thyroid hormone receptor gene expression in first trimester human fetal brain: Comparison betweenbrain medulla and spinal cord

International Journal of Gynecology & ObstetricsVolume 70, Issue S4 p. D145-D145 Molecular genetic Thyroid hormone receptor gene expression in first trimester human fetal brain: Comparison betweenbrain medulla and spinal cord J. Iskaros, J. IskarosSearch for more papers by this authorM. Pickard, M. PickardSearch for more papers by this authorI. Evans, I. EvansSearch for more papers by this authorA. Sinha, A. SinhaSearch for more papers by this author J. Iskaros, J. IskarosSearch for more papers by this authorM. Pickard, M. PickardSearch for more papers by this authorI. Evans, I. EvansSearch for more papers by this authorA. Sinha, A. SinhaSearch for more papers by this author First published: 11 December 2003 https://doi.org/10.1016/S0020-7292(00)84678-0AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume70, IssueS42000Pages D145-D145 RelatedInformation

Spatial and temporal expression of alpha- and beta-thyroid hormone receptor mRNAs, including the beta 2-subtype, in the developing mammalian nervous system

Thyroid hormone exerts profound effects on the developing mammalian brain, and its deficiency can lead to severe mental retardation and motor abnormalities. To identify specific anatomic targets of thyroid hormone action in the developing mammalian nervous system, we examined thyroid hormone receptor gene expression by hybridization histochemistry on serial adjacent sections from 12 stages of the developing rat nervous system. 35S-labeled cRNA probes were generated from divergent sequences of rat alpha 1-, alpha 2-, beta 1-, and beta 2-thyroid hormone receptor and related cDNAs. We found that alpha- and beta-thyroid hormone receptor genes have distinct patterns of spatiotemporal expression in the embryonic and postnatal rat nervous system. alpha 1- and alpha 2-mRNAs were widely expressed in similar patterns; highest levels were found in the fetal neocortical plate, site of cortical neuronal differentiation. In contrast, beta 1-transcripts were restricted in distribution, with prominent expression in zones of neuroblast proliferation such as the germinal trigone and the cortical ventricular layer. Surprisingly, the "pituitary-specific" beta 2-transcript was detected in the developing hippocampus and striatum. Our results suggest that alpha- and beta-thyroid hormone receptors may play distinct functional roles during development of the mammalian nervous system.

A correlation of thyroid hormone receptor gene expression with amphibian metamorphosis.

The expression of the thyroid hormone (TH) receptor genes alpha (TR alpha) and beta (TR beta) in Xenopus laevis begins after the embryo hatches. The TR alpha mRNA increases throughout the premetamorphosis stage of tadpole development, is maximal by prometamorphosis, and falls after climax of metamorphosis to a lower level in frogs. The TR beta mRNA is barely detectable during premetamorphosis. In synchrony with the onset of endogenous TH synthesis by the thyroid gland (prometamorphosis), the level of TR beta mRNA rises in parallel with endogenous TH, reaching a peak at the climax of metamorphosis (stage 61) and drops to approximately 10% of its peak level after metamorphosis. As suggested by this correlation, exogenous TH up-regulates TR beta mRNA as much as 20-fold during premetamorphosis, whereas TH up-regulates TR alpha mRNA by approximately 2-fold during the same period. Up-regulation of TR beta mRNA is the earliest response to exogenous TH by competent tadpoles yet detected.

Sodium butyrate selectively alters thyroid hormone receptor gene expression in GH3 cells.

High-affinity binding of thyroid hormone (T3) to nuclear receptors influences the transcriptional rate of specific genes. The carboxylic acid, sodium butyrate, is known to reduce nuclear binding of T3 in GH3 rat pituitary cels, and this effect correlates with inhibition of T3 responsiveness. Incubation of GH3 cells with 10 mM, but not 1 mM, sodium butyrate abolishes induction of growth hormone gene expression by T3. The relationship between thyroid hormone receptor (TR) depletion and inhibition of T3 action was further investigated by determining the effects of sodium butyrate on TR gene expression. GH3 cells contain mRNAs encoding at least three thyroid hormone receptors (TRs alpha 1, beta 1, and beta 2), as well as a related non-T3 binding repressor or T3 action (c-erbA alpha 2). Remarkably, 10 mM sodium butyrate reduces TR beta 2 mRNA levels by greater than 95% in the presence or absence of T3. The down-regulation of TR beta 2 mRNA occurs at a concentration of sodium butyrate between 5 and 10 mM and is maximal by 8 h of treatment. In contrast, TR beta 1 mRNA levels are unchanged. Furthermore, sodium butyrate has little effect on the mRNAs encoding TR alpha 1 and c-erbA alpha 2. Nuclear run-on assays indicated that sodium butyrate depletes TR beta 2 mRNA by rapidly repressing TR beta 2 gene transcription. In the presence of the transcriptional inhibitor, actinomycin D, the half-life of TR beta 2 mRNA was approximately 3 h in the presence or absence of sodium butyrate. Thus, the reduction in TR number induced by sodium butyrate is likely to be due to the transcriptionally mediated reduction in TR beta 2 mRNA. These data suggest that TR beta 2 has an important physiological role in the regulation of growth hormone gene expression by T3.