SEARCH · PubMed Health

Results for “THYROID HORMONES”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 325 records · Page 18Linked to original sources

PubMed1991

Hepatic UDP-glucuronyltransferase(s) activity toward thyroid hormones in rats: induction and effects on serum thyroid hormone levels following treatment with various enzyme inducers.

Induction of hepatic UDP-glucuronyltransferase(s) (hUDP-GT(s] activity toward thyroid hormones and the relationship between the activity and the serum thyroid hormones or the thyroid stimulating hormone (TSH) level were examined in male Sprague-Dawley rats after four consecutive ip doses of various hepatic enzyme inducers at 75-150 mg/kg/day. hUDP-GT activity toward thyroxine (T4; hUDP-GT-T4) was induced by treatment with beta-naphthoflavone, 3-methylcholanthrene (3-MC), polychlorinated biphenyls, or pregnenolone-16 alpha-carbonitrile. However, no significant induction was observed for isosafrole administration and in the cases of phenobarbital and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane slight decreases were found. The induction profile of hUDP-GT-T4 for these inducers was approximately the same as that of hUDP-GT activity toward triiodothyronine (T3; hUDP-GT-T3), indicating that these two thyroid hormones (T4 and T3) are glucuronidated by the same hUDP-GT(s). Moreover, the induction profile of both hUDP-GT-T4 and hUDP-GT-T3 was similar to that of hUDP-GT toward 1-naphthol, but not chloramphenicol, suggesting that T4 and T3 belong to the so-called group-1 substrates which are preferentially glucuronidated by hUDP-GT(s) inducible by treatment with 3-MC. Decreases in serum T4 levels clearly correlated with an increase in hUDP-GT-T4 activity, indicating that serum T4 levels are directly affected by hUDP-GT-T4 activity. However, no direct correlation between decrease in thyroid hormone levels and compensatory increase in TSH levels was found.

Animals↗

PubMed2005

Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency.

Thyroid hormones are critical for the development and maturation of the central nervous system. Insufficiency of thyroid hormones during development impairs performance on tasks of learning and memory that rely upon the hippocampus and impairs synaptic function in young hypothyroid animals. The present study was designed to determine if perturbations in synaptic function persist in adult euthyroid animals exposed developmentally to insufficient levels of hormone. Pre- and postnatal thyroid hormone insufficiency was induced by administration of 3 or 10 ppm propylthiouracil (PTU) to pregnant and lactating dams via the drinking water from gestation day (GD) 6 until postnatal day (PN) 30. This regimen produced a graded level of hormonal insufficiency in the dam and the offspring. Population spike and population excitatory postsynaptic potentials (EPSP) were recorded at the pyramidal cell layer and the stratum radiatum, respectively, in area CA1 of hippocampal slices from adult male offspring. PTU exposure increased baseline synaptic transmission, reduced paired-pulse facilitation, and increased the magnitude of the population spike long-term potentiation (LTP). Phosphorylation of the extracellular signal-regulated kinases (ERK1 and ERK2) was increased as a function of LTP stimulation in slices from PTU-exposed adult animals. On the other hand, no differences in the basal levels of synaptic proteins implicated in synaptic plasticity (total ERK, synapsin, growth-associated protein-43, and neurogranin) were detected. These results reinforce previous findings of persistent changes in synaptic function and, importantly extend these observations to moderate levels of thyroid hormone insufficiency that do not induce significant toxicity to the dams or the offspring. Such alterations in hippocampal synaptic function may contribute to persistent behavioral deficits associated with developmental hypothyroidism.

Animals↗

PubMed1999

Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH) is a syndrome of variable tissue hyposensitivity to TH. In 191 families, the RTH phenotype has been linked to mutations located in the ligand-binding or hinge domains of the TH receptor (TR) beta gene. The defective TRbeta molecules interfere with the function of the normal TRs to produce dominantly inherited RTH. Of the 65 families with RTH studied in our laboratory, 59 had mutations in the mutagenic region of the TRbeta gene that encompasses exons 7-10. Isolation of a TRbeta PAC (P1 derived artificial chromosome) clone provided the intronic sequences necessary to amplify and sequence the entire TRbeta gene from genomic DNA. Not a single nucleotide substitution, deletion, or insertion was found in all coding and noncoding TRbeta1- and TRbeta2-specific and common exons of the five families with RTH reported herein. Furthermore, linkage analysis using polymorphic markers excluded involvement of the TRbeta and TRalpha genes in two and three of the five families, respectively. The phenotype of RTH in patients without TRbeta gene defects was not different from that in patients with RTH due to TRbeta gene mutations in terms of clinical presentation and reduced responsiveness of the pituitary and peripheral tissues to TH. However, the degree of thyrotroph hyposensitivity to TH appeared to be among the more severe, similar to that of patients with mutant TRbetas that have more than 50-fold reduction of T3 binding affinity and strong dominant negative effect. In these five families and another with non-TRalpha/non-TRbeta RTH, previously identified in our laboratory, evidence for dominant inheritance was secured in two families, and the appearance of a new defect or recessive inheritance was found in the remaining four families. RTH without a structural TRbeta defect occurs in about 10% of families expressing the classic phenotype of TH hyposensitivity, and TRbeta and TRalpha gene involvement has been excluded in 5%. We postulate that a cofactor that interacts with TR is potentially responsible for the manifestation of RTH in these families. As affected subjects are not infertile, the high prevalence of putative neomutations and the low rate of transmission in this non-TR form of RTH may be due to reduced survival of embryos harboring the defect.

Adult↗

PubMed1996

A Purkinje cell protein-2 intronic thyroid hormone response element binds developmentally regulated thyroid hormone receptor-nuclear protein complexes.

Two thyroid hormone response elements (TREs), designated A1 TRE (-295/-268) and B1 TRE (+207/+227), have been identified within the Purkinje cell-expressed Pcp-2 gene. Previous studies have characterized the A1 TRE (Zou et al., 1994). This article analyzes the structural and functional characteristics of the intronic B1 TRE. The B1 sequence contains four overlapping TRE half-sites. The 3' DR4 motif, consisting of the second and forth half-sites, is responsible for the T3 induction observed with the B1 sequence. Gel-shift analysis reveals developmentally regulated complexes that are abundant in the fetus and at birth and then fall precipitously in the neonate bind to B1. The observed time-course of these complexes varies inversely with the rise in Pcp-2 expression, thus raising the possibility that the complexes may represent inhibitory factors. Supershift analysis indicates that endogenous TR alpha 1 is present in the fetal nuclear protein complexes that bind to B1. Competition analysis also indicates the second B1 TRE half-site is important in binding the TR alpha 1-TRAP complexes. These studies suggest that the B1 sequence may bind potential TR alpha 1-TRAP repressor complexes in the fetus, whereas in the neonate, these TRE sites may be involved in the activation of Pcp-2 by binding other TR-TRAP-activating complexes.

Animals↗

PubMed1985

5'-Flanking DNA of the rat growth hormone gene mediates regulated expression by thyroid hormone.

Thyroid hormone has been shown to rapidly stimulate the rate of rat growth hormone gene transcription which parallels the kinetics of binding of 3,5,3'-triiodo-L-thyronine (L-T3) to its nuclear receptor (Yaffe, B. M., and Samuels, H. H. (1984) J. Biol. Chem. 259, 6284-6291). We have constructed a chimeric gene to explore whether the 5'-flanking region of the rat growth hormone gene contains a DNA element which could mediate thyroid hormone control of growth hormone gene expression. The construct consists of 1.8 kilobase pairs of the 5'-flanking region extending 11 nucleotides downstream from the transcription initiation (cap) site ligated to Escherichia coli DNA containing the structural gene for the enzyme xanthine-guanine phosphoribosyltransferase. GC cells, a growth hormone producing rat pituitary cell line, were transfected with this chimeric gene and stable transformants in which the enzyme is regulated by L-T3 were isolated by positive selection using mycophenolic acid and xanthine. These stable transformants develop with relatively high frequency and show marked L-T3 stimulation of xanthine-guanine phosphoribosyltransferase mRNA which is initiated at the cap site of the growth hormone gene. This study provides the first evidence that the 5'-flanking region of the rat growth hormone gene contains a DNA regulatory element which can mediate control of gene expression by thyroid hormone.

Animals↗

PubMed2001

Three Japanese patients from two families with generalized resistance to thyroid hormone with mutations in exon 9 of the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH) is a genetic disorder caused by mutations in the thyroid hormone receptor (TR) beta gene. The mutations are clustered in two regions: exon 9 and exon 10. To date, only one patient with an exon 9 mutation has been reported in Japan. We herein report three patients from two Japanese families with RTH and mutations in exon 9. A 52-year-old woman and her 18-year-old daughter, both with inappropriate secretion of TSH (SITSH) were diagnosed simultaneously with generalized RTH. Molecular analysis revealed a G345D mutation. An 11-year-old girl with SITSH, whose only manifestation was a goiter, had an R338W mutation, which is frequently associated with pituitary RTH. Thus, RTH with mutations in exon 9 of the TR beta gene is not so rare in Japan.

Adolescent↗

PubMed1991

A homozygous deletion in the c-erbA beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor.

Different point mutations have been identified in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene that are associated with variant phenotypes of generalized thyroid hormone resistance (GTHR). In most cases of GTHR, heterozygotes are affected; a single mutant allele results in the inhibition of the function of normal thyroid hormone receptors. We report here a novel genetic abnormality, a 3-basepair (bp) deletion in the T3-binding domain of the beta-receptor in a kindred, S, with GTHR. One patient, S1, was the product of a consanguineous union of two heterozygotes and was homozygous for this defect. Heterozygotes from kindred S harbored a CAC deletion at nucleotides 1295-1297, which resulted in the deduced loss of amino acid residue threonine at codon 332, and they displayed elevated free T4 levels and inappropriately normal TSH levels characteristic of other kindreds with GTHR. However, patient S1, who had two mutant alleles, had markedly elevated TSH and free T4 levels and displayed profound abnormalities in brain development and linear growth. A fibroblast c-erbA beta cDNA extending from codon 175 to stop codon 457 was cloned from patient S1, sequenced, and used to create a full-length mutant cDNA. The kindred S mutant receptor was synthesized in vitro and did not bind T3. This mutant receptor did bind with similar avidity as the wild-type human beta-receptor to thyroid hormone response elements of the human TSH beta (-12 to 43 bp) and rat GH (-188 to -160 bp) genes. Kindred S showed the effect in man of heterozygous and homozygous expression of a dominant negative form of c-erbA beta.

Alleles↗

PubMed2004

Retarded bone growth in thyroid hormone resistance. A clinical study of a large family with a novel thyroid hormone receptor mutation.

OBJECTIVE: Thyroid hormone resistance (RTH) is characterised by variable tissue hyporesponsiveness to thyroid hormone. The disorder is usually caused by mutations in the thyroid hormone receptor beta (TR beta). We describe a large family with this disorder. SUBJECTS AND MEASUREMENT: We identified 36 family members with RTH in four generations by screening relatives of patients with the diagnosis. The diagnosis was verified by identification of a mutation in the thyroid hormone receptor beta (TR beta) gene. Symptoms, clinical findings and laboratory tests of 29 affected individuals were compared with those of 16 first-degree relatives. RESULTS: Bone maturation in children with RTH was delayed. The height was lower both in children and in adults with RTH than in the controls. Children with RTH had lower birth weight than the controls, particularly when the condition was inherited from the father. We did not observe increased prevalence of neuropsychological symptoms associated with RTH in this family. Palpitations and increased pulse rate indicated mild cardiac hyperthyroidism. Direct sequence analysis of the TR beta gene revealed a novel point mutation, a heterozygous transition c.1031G>C in exon 9 theoretically substituting Gly344Ala. CONCLUSIONS: We found evidence of skeletal tissue hypothyroidism that resulted in permanent growth retardation from prenatal to adult life. We found substantial variations in thyroid hormone levels and clinical presentation, but most individuals were without symptoms of thyroid disorder.

Adolescent↗

PubMed1992

A point mutation (Ala229 to Thr) in the hinge domain of the c-erbA beta thyroid hormone receptor gene in a family with generalized thyroid hormone resistance.

Various point mutations in the c-erbA thyroid hormone receptor (TR) beta gene of unrelated kindreds have been reported to be responsible for different phenotypes of generalized thyroid hormone resistance. We now report a new point mutation, Td, in one of two TR beta alleles of three affected members of one family, designated family T. In contrast to the previously described point mutations, all located in the T3-binding domain of the TR beta gene, mutation Td was identified in the carboxy-terminal part of the hinge domain. Direct sequencing of the polymerase chain reaction-amplified whole coding region of the patients' fibroblast TR beta genes displayed a single guanine to adenine transition at cDNA nucleotide position 985. This altered alanine (GCC) to threonine (ACC) in codon 229. Garnier prediction of the consequence of the mutation indicated an altered secondary structure. The G----A nucleotide substitution was not present in 80 random TR beta alleles, suggesting that this point mutation is responsible for generalized thyroid hormone resistance in family T. The in vitro expressed mutant TR beta was shown to bind with high affinity to various thyroid hormone response elements. However, the affinity of the TR beta to bind to T3 was reduced 3-fold, indicating that the hinge domain of the TR beta is important for full ligand-binding activity. Moreover, it seems that multiple subdomains of the TR beta interact cooperatively to achieve optimal T3 activity.

Alleles↗

PubMed1986

The effect of double filtration plasmapheresis on thyroid hormone economy and thyroid function.

Five cases of rheumatoid arthritis (RA), two cases of systemic lupus erythematosus (SLE), a case of mixed connective tissue disease (MCTD), and a case of cold urticaria were treated with double filtration plasmapheresis (DFP). Each aliquot of plasma was obtained at three different points of the DEP circuit during the treatment and concentrations of thyroid hormones as well as thyroxine binding globulin (TBG) were measured. Despite the removal of considerable amounts of triiodothyronine (T3), thyroxine (T4), and TBG from the plasma, levels of plasma free T3 (FT3) and free T4 (FT4) before and immediately after DFP treatment were not significantly different. These results indicate that DEP therapy rarely affects plasma concentration of active thyroid hormones in patients who undergo such therapy.

Adolescent↗

PubMed1994

Three new mutations of thyroid hormone receptor-beta associated with resistance to thyroid hormone.

Three novel point mutations at nucleotides 1249, 1282, and 1614 (exons 9 and 10) of the human thyroid hormone receptor-beta gene were observed in six individuals affected by the syndrome of resistance to thyroid hormone. All three mutations occurred in a heterozygous pattern and caused the following changes in the mature form of the receptor protein: Asp322 to Asn, Glu333 to Gln, and Lys443 to Asn, respectively. The first and third point mutations arose in two unrelated families from eastern Sicily, whereas the second concerned an individual from southern Calabria, apparently presenting a sporadic form of the resistance syndrome. The clinical and biochemical features of resistance to thyroid hormone, both before and after the administration of thyroid hormones, highlight the striking intrafamilial heterogeneity in the phenotypical presentation of the syndrome.

Adolescent↗

PubMed2006

Identification and characterization of RanBPM, a novel coactivator of thyroid hormone receptors.

Thyroid hormone receptors (TRs) are transcription factor members of the nuclear receptor superfamily. The transcriptional activity of TRs is controlled by thyroid hormones and cell-specific coregulators. Using the yeast two-hybrid system, we identified RanBPM as a new protein partner for TRs. RanBPM was initially discovered as an interacting partner for Ran, and was also shown to be a protein partner and coactivator of the androgen receptor. The novel interaction between RanBPM and TR isoforms was addressed by glutathione-S-transferase (GST) pull-down assays and co-immunoprecipitation in intact mammalian cells, where RanBPM was shown to bind TRs in a ligand-independent fashion. We also studied the regions implicated in the interaction with deletion mutants: the principal interacting region of RanBPM is comprised within its carboxyl-terminal end and the TR DNA-binding domain is sufficient to mediate the interaction. To investigate the potential role of RanBPM in thyroid hormone action, transient transfections with luciferase reporter genes were performed in CV-1 cells. We found that the over-expression of RanBPM increases the activation of TRETK- and DR+4-positive thyroid hormone response elements. Interestingly, over-expression of the truncated protein RanBPM55, which lacks the N-terminal polyglutaminated region but binds TRs, decreased the fold activation by almost 80%. Furthermore, we performed competition assays using transient transfection of RanBPM and increasing amounts of RanBPM55. This revealed that the stimulating effect on TR transactivation by the full-length protein is inhibited in a dose-dependent fashion by RanBPM55. This suggests that although the polyglutaminated region of RanBPM is not required for the binding to TRs, it is required for the stimulation of TR transactivation. Taken together, our results provide evidence that RanBPM is a potent novel coactivator for thyroid hormone receptors.

Cell Line↗

PubMed1992

Correlations of language abnormalities with localization of mutations in the beta-thyroid hormone receptor in 13 kindreds with generalized resistance to thyroid hormone: identification of four new mutations.

Generalized resistance to thyroid hormone is an inherited disease characterized by unresponsiveness of pituitary and peripheral tissues to thyroid hormone. Genetic analysis of several kindreds linked this syndrome to the gene for the beta-form of the thyroid hormone receptor, and this led to the subsequent identification of various mutations in the ligand-binding domain of this receptor. In this region we now have found 4 new point mutations with reduced T3-binding affinities from separate kindreds by direct sequencing of polymerase chain reaction products. Similar to previously studied kindreds, the reduction in T3 binding of these four kindreds ranged from 2.5- to 5-fold, indicating that these are not neutral polymorphisms. Furthermore, the pattern of inheritance of these 4 kindreds is familial in 2, sporadic in 1, and unknown in 1. To date, 20 distinct mutations have been identified, of which 18 are clustered in 2 distinct topographical regions: 11 are within the tau i/dimerization subdomains of exon 9, and 7 are within the L2 subdomain of exon 10. The 4 newly identified mutations coupled to the 9 mutations our laboratory has previously identified provide new insights into the clinical aspects of generalized resistance to thyroid hormone. Kindreds with mutations in exon 9 compared with those in exon 10 have significantly more problems in language development, as manifested by articulation problems and/or wide discrepancies in verbal and performance IQs. Interestingly, marked variability in language deficiency as well as other clinical patterns were seen not only between kindreds but also within a kindred. Further identification and clinical correlations of new mutations will continue to enhance our understanding of the structure/function relationships and physiological role of the human thyroid hormone receptor.

Adolescent↗

PubMed2002

Effect of coenzymes and thyroid hormones on the dual activities of Xenopus cytosolic thyroid-hormone-binding protein (xCTBP) with aldehyde dehydrogenase activity.

A cytosolic thyroid-hormone-binding protein (xCTBP), predominantly responsible for the major binding activity of T3 in the cytosol of Xenopus liver, has been shown to be identical to aldehyde dehydrogenase class 1 (ALDH1) [Yamauchi, K., Nakajima, J., Hayashi, H., Horiuchi, R. & Tata, J.R. (1999) J. Biol. Chem. 274, 8460-8469]. Within this paper we surveyed which signaling, and other, compounds affect the thyroid hormone binding activity and aldehyde dehydrogenase activity of recombinant Xenopus ALDH1 (xCTBP/xALDH1) while examining the relationship between these two activities. NAD+ and NADH (each 200 microm), and two steroids (20 microm), inhibit significantly the T3-binding activity, while NADH and NADPH (each 200 microm), and iodothyronines (1 microm), inhibit the ALDH activity. Scatchard analysis and kinetic studies of xCTBP/xALDH1 indicate that NAD+ and T3 are noncompetitive inhibitors of thyroid-hormone-binding and ALDH activities, respectively. These results indicate the formation of a ternary complex consisting of the protein, NAD+ and thyroid hormone. Although the in vitro studies indicate that NAD+ and NADH markedly decrease T3-binding to xCTBP/xALDH1 at approximately 10-4 m, a concentration equal to the NAD content in various Xenopus tissues, photoaffinity-labeling of [125I]T3 using cultured Xenopus cells demonstrates xCTBP/xALDH1 bound T3 within living cells. These results raise the possibility that an unknown factor(s) besides NAD+ and NADH may modulate the thyroid-hormone-binding activity of xCTBP/xALDH1. In comparison, thyroid hormone, at its physiological concentration, would poorly modulate the enzyme activity of xCTBP/xALDH1.

Aldehyde Dehydrogenase↗

PubMed2005

Design and synthesis of complementing ligands for mutant thyroid hormone receptor TRbeta(R320H): a tailor-made approach toward the treatment of resistance to thyroid hormone.

The thyroid hormone receptors (TR) are ligand-dependant transcription factors that regulate key genes involved in metabolic regulation, thermogenesis and development. Resistance to thyroid hormone (RTH) is a genetic disease associated with mutations to TRbeta that lack or show reduced responsiveness to thyroid hormone (triiodothyronine). Previously we reported that the neutral alcohol-based thyromimetic HY-1 can selectively restore activity to a functionally impaired form of TR associated with RTH without over-stimulating TRalpha, which has been associated with undesirable side effects. Two new series of tetrazole and thiazolidinedione based ligands were evaluated for their ability to recover potency and efficacy to three of the most common RTH-associated mutants, TRbeta(R320C), TRbeta(R320H), and TRbeta(R316H), in cell based assays. A new thiazolidinedione based ligand AH-9 was identified, which has near wild-type potency (EC(50)=0.54 nM) to TRbeta(R320C) and TRbeta(R320H). Significantly, AH-9 is equipotent toward TRalpha(wt), TRbeta(wt), TRbeta(R320C), and TRbeta(R320H), suggesting that AH-9 may have the potential to restore the normal homeostatic balance of thyroid hormone actions in patients or models harboring these mutations.

Ligands↗

PubMed2001

Thyroid hormone--sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform--specific.

In newborns and small mammals, cold-induced adaptive (or nonshivering) thermogenesis is produced primarily in brown adipose tissue (BAT). Heat production is stimulated by the sympathetic nervous system, but it has an absolute requirement for thyroid hormone. We used the thyroid hormone receptor-beta--selective (TR-beta--selective) ligand, GC-1, to determine by a pharmacological approach whether adaptive thermogenesis was TR isoform--specific. Hypothyroid mice were treated for 10 days with varying doses of T3 or GC-1. The level of uncoupling protein 1 (UCP1), the key thermogenic protein in BAT, was restored by either T3 or GC-1 treatment. However, whereas interscapular BAT in T3-treated mice showed a 3.0 degrees C elevation upon infusion of norepinephrine, indicating normal thermogenesis, the temperature did not increase (<0.5 degrees C) in GC-1--treated mice. When exposed to cold (4 degrees C), GC-1--treated mice also failed to maintain core body temperature and had reduced stimulation of BAT UCP1 mRNA, indicating impaired adrenergic responsiveness. Brown adipocytes isolated from hypothyroid mice replaced with T3, but not from those replaced with GC-1, had normal cAMP production in response to adrenergic stimulation in vitro. We conclude that two distinct thyroid-dependent pathways, stimulation of UCP1 and augmentation of adrenergic responsiveness, are mediated by different TR isoforms in the same tissue.

Acetates↗

PubMed2005

Thyroid hormone induces cardiac myocyte hypertrophy in a thyroid hormone receptor alpha1-specific manner that requires TAK1 and p38 mitogen-activated protein kinase.

Alterations in TR [thyroid hormone (TH) receptor]1 isoform expression have been reported in models of both physiologic and pathologic cardiac hypertrophy as well as in patients with heart failure. In this report, we demonstrate that TH induces hypertrophy as a direct result of binding to the TRalpha1 isoform and, moreover, that overexpression of TRalpha1 alone is also associated with a hypertrophic phenotype, even in the absence of ligand. The mechanism of TH and TRalpha1-specific hypertrophy is novel for a nuclear hormone receptor and involves the transforming growth factor beta-activated kinase (TAK1) and p38. Mitigating TRalpha1 effects, both TRalpha2 and TRbeta1 attenuate TRalpha1-induced myocardial growth and gene expression by diminishing TAK1 and p38 activities, respectively. These findings refine our previous observations on TR expression in the hypertrophied and failing heart and suggest that manipulation of thyroid hormone signaling in an isoform-specific manner may be a relevant therapeutic target for altering the pathologic myocardial program.

Adenoviridae↗

PubMed1997

The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production.

The diverse functions of thyroid hormones are thought to be mediated by two nuclear receptors, T3R alpha1 and T3R beta, encoded by the genes T3R alpha and T3R beta respectively. The T3R alpha gene also produces a non-ligand-binding protein T3R alpha2. The in vivo functions of these receptors are still unclear. We describe here the homozygous inactivation of the T3R alpha gene which abrogates the production of both T3R alpha1 and T3R alpha2 isoforms and that leads to death in mice within 5 weeks after birth. After 2 weeks of life, the homozygous mice become progressively hypothyroidic and exhibit a growth arrest. Small intestine and bones showed a strongly delayed maturation. In contrast to the negative regulatory function of the T3R beta gene on thyroid hormone production, our data show that the T3R alpha gene products are involved in up-regulation of thyroid hormone production at weaning time. Thus, thyroid hormone production might be balanced through a positive T3R alpha and a negative T3R beta pathway. The abnormal phenotypes observed on the homozygous mutant mice strongly suggest that the T3R alpha gene is essential for the transformation of a mother-dependent pup to an 'adult' mouse. These data define crucial in vivo functions for thyroid hormones through a T3R alpha pathway during post-natal development.

Acetylcholine↗