Disease relevance of Thrb

• Although hypothyroidism causes cochlear malformation, there was no evidence of this in Thrb-/- mice [1].
• In contrast, TR beta 2-null mice exhibit no evidence of hearing impairment, indicating that TR beta 1 and TR beta 2 subserve divergent roles in the regulation of auditory function [2].
• TR beta-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a) [3].
• Biallelic inactivation of the thyroid hormone receptor beta1 gene in early stage breast cancer [4].
• Replication-defective recombinant adenoviruses were constructed that express the human wild-type (WT) TR beta, a human mutant TR beta identified in a family with RTH, and luciferase under the control of thyroid hormone (Luc) [5].

High impact information on Thrb

• Here we delete Thrb (encoding Tr beta 2) in mice, causing the selective loss of M-cones and a concomitant increase in S-opsin immunoreactive cones [6].
• Thrb-/- mice provide a model for the human endocrine disorder of resistance to thyroid hormone (RTH), which is typically associated with dominant mutations in Tr beta [1].
• The auditory-evoked brainstem response (ABR) in Thrb-/- mice, although greatly diminished, displayed normal waveforms, which suggested that the primary defect resides in the cochlea [1].
• In target tissues, T(4) is enzymatically deiodinated to 3,5,3'-triiodothyronine (T(3)), a high-affinity ligand for the nuclear TH receptors TR alpha and TR beta, whose activation controls normal vertebrate development and physiology [7].
• However, TR-betaGS/GS mutant mice maintained normal hearing at certain frequencies and did not display significant outer hair cell loss, in contrast to TR-beta-/- mice [8].

Chemical compound and disease context of Thrb

• Mice with targeted disruption of the entire TR beta locus (TR beta-null) exhibit elevated thyroid hormone levels as a result of abnormal central regulation of thyrotropin, and also develop profound hearing loss [2].

Biological context of Thrb

• Differences in the gene expression patterns of Thra/Thrb double-knockout mice and Th-deprived wild-type mice show that absence of receptor and of hormone can have different effects [9].
• We determined the relative roles of TRalpha1 and TRbeta1 in the thyroid hormone effect on testicular development and Sertoli cell proliferation using Thra knockout (TRalphaKO), Thrb knockout (TRbetaKO), and wild-type (WT) mice [10].
• However, a potent function for the Thra(tm2) allele is revealed upon its introduction into Thrb(tm1/tm1) mice, where it suppresses the auditory and thyroid phenotypes caused by loss of TR beta [11].
• The human syndrome of resistance to thyroid hormone (RTH) is associated with dominant mutations in the thyroid hormone receptor beta (TR beta) gene that generate mutant receptors with impaired binding for T3 [12].
• Wild type TR beta 1 and TR beta 2 mediated T3-inducible transactivation in cotransfection assays; this, however, was abolished in both mutants [12].

Anatomical context of Thrb

• Whereas TR alpha 1 and TR beta 1 are widely expressed, expression of the TR beta 2 isoform is mainly limited to the pituitary, triiodothyronine-responsive TRH neurons, the developing inner ear, and the retina [2].
• Thus, isolated TR-beta deficiency in TRH paraventricular hypothalamic nucleus neurons and impaired function of all TRs in the pituitary recapitulate the baseline hormonal disturbances that characterize mice with complete absence of all TRs [13].
• Changes in cardiac gene expression, cardiac muscle contractility, and electrocardiogram are compatible with a hypothyroid cardiac phenotype despite normal T3 levels, indicating a dominant negative effect of the T3Rbeta mutant [14].
• TR alpha 1 represents 70% and TR beta 1 represents the remaining 30% of TR in ventricular myocytes, and its role in cardiac function is not well established [15].
• To determine the functions of the alpha 1 and beta 1 thyroid hormone receptors (TRs) in neural differentiation, we have established stable transfected neuronal cell lines (Neuro-2a) that overexpress either TR alpha 1 or TR beta 1 [16].

Associations of Thrb with chemical compounds

• Also, thyroid-stimulating hormone (TSH), which is released by pituitary thyrotropes and which is normally suppressed by increased levels of thyroid hormone, was present at elevated levels in homozygous mutant (Thrb-/-) mice [17].
• Wild type TR beta 1 and TR beta 2 bound similarly as homodimers and as heterodimers with retinoid X receptors to T3-responsive elements consisting of a direct repeat with 4-base pair spacing or an everted repeat [12].
• TR beta deficient (TR beta-/-) and wild-type (TR beta+/+) mice of the same strain were deprived of thyroid hormone by feeding them a low iodine diet containing propylthiouracil and were then treated with different doses of L-T3 and L-T4 [18].
• Critical role for thyroid hormone receptor beta2 in the regulation of paraventricular thyrotropin-releasing hormone neurons [19].
• The TR beta subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TR alpha appears to be more important for control of heart rate (HR) [3].

Physical interactions of Thrb

• Electromobility shift analysis revealed that LXR/RXR heterodimers bound to the DR+4 element in the presence of MUT but not WT TR-beta [20].

Regulatory relationships of Thrb

• In summary, although TR beta is expressed at much lower levels in all regions of the heart than TR alpha 1, expression of the strong dominant negative TR beta PV mutant results in decreased contractile function and heart rate [15].
• 3,5,3'-Triiodothyronine (T3) treatment of cells that overexpress TR beta 1 blocks proliferation by an arrest of cells in G0/G1 and induces morphological and functional differentiation of Neuro-2a cells as indicated by the marked increase in the number of perisomatal filopodia-like neurites and in acetylcholinesterase (AChE) activity [16].
• Differential effects of leptin and refeeding on the fasting-induced decrease of pituitary type 2 deiodinase and thyroid hormone receptor beta2 mRNA expression in mice [21].

Other interactions of Thrb

• Thyrotropin regulation by thyroid hormone in thyroid hormone receptor beta-deficient mice [18].
• In transfection studies, WT but not MUT TR-beta antagonized induction of this promoter by LXR-alpha [20].
• Thus, the present studies show that a coactivator such as SRC-1 could modulate the in vivo action of TR beta mutants in a tissue-dependent manner [22].
• Oct-1, silencer sequence, and GC box regulate thyroid hormone receptor beta1 promoter [23].
• In this study, we examined cholesterol metabolism in a thyroid hormone receptor beta (TR-beta) mutant mouse model of resistance to thyroid hormone [20].

Analytical, diagnostic and therapeutic context of Thrb

• We used 48 complementary DNA microarrays to examine hepatic gene expression profiles of wild-type and Thra and Thrb knockout mice under different Th conditions: no treatment, treatment with 3,3',5-triiodothyronine (T(3)), Th-deprivation using propylthiouracil (PTU), and treatment with a combination of PTU and T(3) [9].
• The polymerase chain reaction was used to amplify additional cDNAs for the specific 5' domains of the mouse TR beta 1 and the pituitary-specific TR beta 2 amino-terminal variant [24].
• In this study, we used gene-targeting techniques to mutate the TR-beta locus within its activation function-2 (AF-2) domain (E457A) [25].
• In vivo chromatin immunoprecipitation assays demonstrated that T3 induced thyroid hormone receptor-beta recruitment to Site2 [26].
• TR beta 1 messenger RNA was detected by RT-PCR in the developing limbs and face [27].

References