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Gene Review

Thrb  -  thyroid hormone receptor beta

Mus musculus

Synonyms: Erba2, Nr1a2, Nuclear receptor subfamily 1 group A member 2, T3R[b], T3Rbeta, ...
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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


Analytical, diagnostic and therapeutic context of Thrb


  1. Thyroid hormone receptor beta is essential for development of auditory function. Forrest, D., Erway, L.C., Ng, L., Altschuler, R., Curran, T. Nat. Genet. (1996) [Pubmed]
  2. Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system. Abel, E.D., Boers, M.E., Pazos-Moura, C., Moura, E., Kaulbach, H., Zakaria, M., Lowell, B., Radovick, S., Liberman, M.C., Wondisford, F. J. Clin. Invest. (1999) [Pubmed]
  3. Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Grover, G.J., Mellström, K., Ye, L., Malm, J., Li, Y.L., Bladh, L.G., Sleph, P.G., Smith, M.A., George, R., Vennström, B., Mookhtiar, K., Horvath, R., Speelman, J., Egan, D., Baxter, J.D. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. Biallelic inactivation of the thyroid hormone receptor beta1 gene in early stage breast cancer. Li, Z., Meng, Z.H., Chandrasekaran, R., Kuo, W.L., Collins, C.C., Gray, J.W., Dairkee, S.H. Cancer Res. (2002) [Pubmed]
  5. A mouse model of resistance to thyroid hormone produced by somatic gene transfer of a mutant thyroid hormone receptor. Hayashi, Y., Mangoura, D., Refetoff, S. Mol. Endocrinol. (1996) [Pubmed]
  6. A thyroid hormone receptor that is required for the development of green cone photoreceptors. Ng, L., Hurley, J.B., Dierks, B., Srinivas, M., Saltó, C., Vennström, B., Reh, T.A., Forrest, D. Nat. Genet. (2001) [Pubmed]
  7. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Scanlan, T.S., Suchland, K.L., Hart, M.E., Chiellini, G., Huang, Y., Kruzich, P.J., Frascarelli, S., Crossley, D.A., Bunzow, J.R., Ronca-Testoni, S., Lin, E.T., Hatton, D., Zucchi, R., Grandy, D.K. Nat. Med. (2004) [Pubmed]
  8. Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo. Shibusawa, N., Hashimoto, K., Nikrodhanond, A.A., Liberman, M.C., Applebury, M.L., Liao, X.H., Robbins, J.T., Refetoff, S., Cohen, R.N., Wondisford, F.E. J. Clin. Invest. (2003) [Pubmed]
  9. Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice. Yen, P.M., Feng, X., Flamant, F., Chen, Y., Walker, R.L., Weiss, R.E., Chassande, O., Samarut, J., Refetoff, S., Meltzer, P.S. EMBO Rep. (2003) [Pubmed]
  10. Regulation of neonatal Sertoli cell development by thyroid hormone receptor alpha1. Holsberger, D.R., Kiesewetter, S.E., Cooke, P.S. Biol. Reprod. (2005) [Pubmed]
  11. Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor alpha gene. Ng, L., Rüsch, A., Amma, L.L., Nordström, K., Erway, L.C., Vennström, B., Forrest, D. Hum. Mol. Genet. (2001) [Pubmed]
  12. N-terminal variants of thyroid hormone receptor beta: differential function and potential contribution to syndrome of resistance to thyroid hormone. Ng, L., Forrest, D., Haugen, B.R., Wood, W.M., Curran, T. Mol. Endocrinol. (1995) [Pubmed]
  13. Dominant inhibition of thyroid hormone action selectively in the pituitary of thyroid hormone receptor-beta null mice abolishes the regulation of thyrotropin by thyroid hormone. Abel, E.D., Moura, E.G., Ahima, R.S., Campos-Barros, A., Pazos-Moura, C.C., Boers, M.E., Kaulbach, H.C., Forrest, D., Wondisford, F.E. Mol. Endocrinol. (2003) [Pubmed]
  14. Altered cardiac phenotype in transgenic mice carrying the delta337 threonine thyroid hormone receptor beta mutant derived from the S family. Gloss, B., Sayen, M.R., Trost, S.U., Bluhm, W.F., Meyer, M., Swanson, E.A., Usala, S.J., Dillmann, W.H. Endocrinology (1999) [Pubmed]
  15. Cardiac expression and function of thyroid hormone receptor beta and its PV mutant. Swanson, E.A., Gloss, B., Belke, D.D., Kaneshige, M., Cheng, S.Y., Dillmann, W.H. Endocrinology (2003) [Pubmed]
  16. Overexpression of the beta 1 thyroid receptor induces differentiation in neuro-2a cells. Lebel, J.M., Dussault, J.H., Puymirat, J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  17. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function. Forrest, D., Hanebuth, E., Smeyne, R.J., Everds, N., Stewart, C.L., Wehner, J.M., Curran, T. EMBO J. (1996) [Pubmed]
  18. Thyrotropin regulation by thyroid hormone in thyroid hormone receptor beta-deficient mice. Weiss, R.E., Forrest, D., Pohlenz, J., Cua, K., Curran, T., Refetoff, S. Endocrinology (1997) [Pubmed]
  19. Critical role for thyroid hormone receptor beta2 in the regulation of paraventricular thyrotropin-releasing hormone neurons. Abel, E.D., Ahima, R.S., Boers, M.E., Elmquist, J.K., Wondisford, F.E. J. Clin. Invest. (2001) [Pubmed]
  20. Cross-talk between thyroid hormone receptor and liver X receptor regulatory pathways is revealed in a thyroid hormone resistance mouse model. Hashimoto, K., Cohen, R.N., Yamada, M., Markan, K.R., Monden, T., Satoh, T., Mori, M., Wondisford, F.E. J. Biol. Chem. (2006) [Pubmed]
  21. 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. Boelen, A., Kwakkel, J., Vos, X.G., Wiersinga, W.M., Fliers, E. J. Endocrinol. (2006) [Pubmed]
  22. Modulation by steroid receptor coactivator-1 of target-tissue responsiveness in resistance to thyroid hormone. Kamiya, Y., Zhang, X.Y., Ying, H., Kato, Y., Willingham, M.C., Xu, J., O'Malley, B.W., Cheng, S.Y. Endocrinology (2003) [Pubmed]
  23. Oct-1, silencer sequence, and GC box regulate thyroid hormone receptor beta1 promoter. Nagasawa, T., Takeda, T., Minemura, K., DeGroot, L.J. Mol. Cell. Endocrinol. (1997) [Pubmed]
  24. Isolation and characterization of mouse complementary DNAs encoding alpha and beta thyroid hormone receptors from thyrotrope cells: the mouse pituitary-specific beta 2 isoform differs at the amino terminus from the corresponding species from rat pituitary tumor cells. Wood, W.M., Ocran, K.W., Gordon, D.F., Ridgway, E.C. Mol. Endocrinol. (1991) [Pubmed]
  25. Negative regulation by thyroid hormone receptor requires an intact coactivator-binding surface. Ortiga-Carvalho, T.M., Shibusawa, N., Nikrodhanond, A., Oliveira, K.J., Machado, D.S., Liao, X.H., Cohen, R.N., Refetoff, S., Wondisford, F.E. J. Clin. Invest. (2005) [Pubmed]
  26. Mouse sterol response element binding protein-1c gene expression is negatively regulated by thyroid hormone. Hashimoto, K., Yamada, M., Matsumoto, S., Monden, T., Satoh, T., Mori, M. Endocrinology (2006) [Pubmed]
  27. Thyroid hormone receptor beta 1 expression in developing mouse limbs and face. Nagasawa, T., Suzuki, S., Takeda, T., DeGroot, L.J. Endocrinology (1997) [Pubmed]
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