Disease relevance of Thra

• Surprisingly, however, hypothyroidism normalized the appearance of these markers in the P11 mutants, suggesting that liganded TR beta is detrimental to astroglial cell differentiation in the absence of TR alpha 1 [1].
• Electrophoretic mobility shift assay experiments showed that Escherichia coli expressed and affinity purified TR alpha bound to the skeletal alpha-actin TRE in a sequence specific manner [2].
• The apparent close proximity of the c-erbA sequences to the chromosomal breakpoints in these two leukemias suggests a possible role for this oncogene homologue in the development of these neoplasms [3].
• Because the c-erbA locus is altered in several types of carcinoma, an altered or deregulated TR alpha-1 expression may also be important for breast cancer development and metastasis [4].
• Using a footprinting technique and Spodoptera frugiperda 9 (Sf9) nuclear extract infected with baculovirus expressing TR alpha, we have identified a single DNA-binding site (-186/-163) for the receptor [5].

Psychiatry related information on Thra

• Thra(tm2/tm2) mice have normal auditory thresholds indicating that TR alpha 2 is dispensable for hearing, and have only marginally reduced thyroid activity [6].

High impact information on Thra

• Nucleotide sequence analysis predicts that the ear71 protein is a human counterpart of the chicken c-erbA protein, a molecule closely related or identical to thyroid hormone receptor [7].
• 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 [8].
• 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 [9].
• They also suggest that T3Rbeta receptors are dispensable but can partially substitute for T3Ralpha [10].
• T3Ralpha-/- mice had abnormal intestinal morphology, assessed by a decrease in the number of epithelial cells along the crypt-villus axis and a decrease in proliferating crypt cells [10].

Chemical compound and disease context of Thra

• As early-onset hypothyroidism produces audiogenic seizure susceptibility (AGS) in rodents, the role of TR alpha 1 and TR beta thyroid hormone receptors in AGS was investigated [11].
• Regulation of thyroid hormone receptor and c-erbA mRNA levels by butyrate in neuroblastoma (N2A) and glioma (C6) cells [12].

Biological context of Thra

• 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 [13].
• 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 [14].
• T3 increased metabolic rate [whole body oxygen consumption (MVO2)] in both WT and TR alpha-/- mice, but the effect in the TR alpha 1-/- mice at the highest dose was half that of the WT mice [15].
• Transfection experiments with increasing amounts of expression vectors for either TR alpha or RXR alpha resulted in up to 6-fold enhancement of CAT transcription [16].
• Mutagenesis of the myoD TRE indicated that the sequence of the direct repeats (AGGTCA) and the 4 nucleotide gap were necessary for efficient binding to the TR alpha/RXR alpha heterodimeric complex [17].

Anatomical context of Thra

• TRalpha1 and TRbeta, which act as hormone-activated transcription factors, are encoded by the Thra and Thrb genes, respectively, and both are expressed in the developing cochlea [18].
• To determine whether the decreased CMR(glc) in mutant TR alpha 1(PV/+) mice reflected lesser synaptic density or reduced functional activity in existing synapses, we stimulated vibrissae unilaterally and measured CMR(glc) bilaterally in four stations of the whisker-to-barrel cortex pathway [19].
• Aberrant maturation of astrocytes in thyroid hormone receptor alpha 1 knockout mice reveals an interplay between thyroid hormone receptor isoforms [1].
• We studied the effect of the c-erbA/TR alpha proto-oncogene encoding a functional T(3) receptor (TR alpha 1), of its ligand T(3), and of its retroviral, mutated counterpart, the v-erbA oncogene, on the proliferation capacity of nontumorigenic mammary epithelial cells (EpH4) [20].
• CONCLUSIONS: These data describe for the first time a direct effect of TH through the T3Ralpha-receptor subtypes on postnatal intestinal mucosa maturation [10].

Associations of Thra with chemical compounds

• These genes-Rara, Thra, and Erbb2- encode receptors for retinoic acid, thyroxine, and neuregulin, respectively [21].
• 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) [13].
• T3 had equivalent potency for cholesterol reduction in WT and TR alpha-/- mice [15].
• We recently found that glucose utilization (CMR(glc)) is markedly depressed throughout the brain in mice with targeted mutations in thyroid hormone receptor alpha1 (TR alpha 1), but not TR beta [19].
• We generated mice with a point mutation in the thyroid hormone receptor alpha (TRalpha) gene producing a dominant-negative TRalpha mutant receptor with a proline to histidine substitution (P398H) [22].

Regulatory relationships of Thra

• 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 [23].
• Unliganded c-erbA/thyroid hormone receptor induces trkB expression in neuroblastoma cells [24].
• Also, the low invasion capacity of parental B3.1 and c-erbA-expressing cells (B3.1 + TR alpha 1) was enhanced by exogenously added PDGF BB [25].
• Overexpression of c-erbA proto-oncogene enhances myogenic differentiation [26].
• Our results demonstrate that a large majority of the ER alpha-positive neurons also expresses TR alpha 1 and TR alpha 2 mRNAs [27].

Other interactions of Thra

• In conclusion our data suggest that the TRE in the helix loop helix gene, myoD, is a target for the direct heterodimeric binding of TR alpha and RXR alpha/gamma [17].
• As reported recently, Pax8(-/-) mice can also be rescued and survive to adulthood by the additional elimination of the entire thyroid hormone receptor alpha (TRalpha) gene, yielding Pax8(-/-)TRalpha(o/o) double-knockout animals [28].
• To define the origin of the bone marrow development defect, chimeric animals between T3R alpha-/- and Rag1-/- mice were generated [29].
• To determine the cause of the disproportionate elevation of D1, TR alpha1+/+ and TR alpha1(PV/+) mice were rendered hypothyroid and then treated with T3 [30].
• In contrast, B3.1 cells responded to basic fibroblast growth factor better than B3.1 + TR alpha 1 or B3.1 + v-erbA cells [31].

Analytical, diagnostic and therapeutic context of Thra

• Baseline CMR(glc) (unstimulated side) was markedly lower in all four stations in the TR alpha 1(PV/+) mutants than in wild-type controls, even though Northern blot and immunohistochemical examinations showed normal Na(+),K(+)-adenosine triphosphatase expression and neuronal differentiation [19].
• Western blot analysis indicated that TR alpha 1 was constitutively expressed during C2C12 differentiation [17].
• Electrophoretic mobility shift assays showed that the repeat element was able to form retarded complexes with TR alpha homodimers, as well as with TR alpha-RXR alpha heterodimers [16].
• There are differences between TR alpha 1-/-beta-/- mice (receptor deficient) and the hypothyroid animal model (ligand deficient) [32].
• Using XENOPUS: oocyte microinjection assays, we show that there are two coexisting mechanisms for nuclear entry of TR alpha [33].

References