Lessons Learned from TR-β Mutant Mice

  • Fredric E. Wondisford
Part of the Endocrine Updates book series (ENDO, volume 22)


Thyroid hormone receptors (TR) are cellular homologues of the viral erythroblastic leukemia oncogene (v-erbA). TRs (c-erbA isoforms) are derived from two separate gene loci in mammals: α and β1. The α locus in humans is located on chromosome 17 (17q11.2) and the β locus is on chromosome 3 (3p24.3). The TR-α gene undergoes alternative splicing generating two c-erbA isoforms: TR-αl and α2. TR-α1 is a bona fide thyroid hormone receptor, whereas alternative splicing of the C-terminus of α2 generates a non-T3 binding isoform. The TR-β gene generates two major isoforms due to alternative promoter utilization: TR-β1 and TR-β2. This results in two beta thyroid hormone receptors with different amino termini (Figure 1).


Thyroid Hormone Outer Hair Cell Congenital Hypothyroidism Thyroid Hormone Receptor External Granular Layer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lazar, M.A. 1993. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev. 14:184–193.PubMedGoogle Scholar
  2. 2.
    Williams GR. 2000 Cloning and characterization of two novel thyroid hormone receptor beta isoforms. Mol Cell Biol 20:8329–42.PubMedCrossRefGoogle Scholar
  3. 3.
    Hodin, R.A., Lazar, M.A., Wintman, B.I., Darling, D.S., Koenig, R.J., Larsen, P.R., Moore, D.D., and Chin, W.W. 1989. Identification of a thyroid hormone receptor that is pituitary-specific. Science. 244:76–79.PubMedCrossRefGoogle Scholar
  4. 4.
    Bradley, D.J., Towle, H.C., and Young, W.S. 3rd. 1994. Alpha and beta thyroid hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoformspecific transcriptional regulation in vivo. Proc Natl Acad Sci USA. 91:439–443.PubMedCrossRefGoogle Scholar
  5. 5.
    Safer JD, Langlois MF, Cohen R, Monden T, D John-Hope, Madura J, Hollenberg AN, Wondisford FE. 1997 Isoform variable action among thyroid hormone receptor mutants provides insight into pituitary resistance to thyroid hormone, Mol Endocrinol, 11: 16–26.PubMedCrossRefGoogle Scholar
  6. 6.
    Yen, P.M. 2001. Physiological and molecular basis of thyroid hormone action. Physiol Rev 81:1097–1142.PubMedGoogle Scholar
  7. 7.
    Jepsen, K, and Rosenfeld M.G. 2002. Biological roles and mechanistic actions of corepressor complexes. J Cell Science 115:689–698.PubMedGoogle Scholar
  8. 8.
    Brent, G.A., Larsen, P.R., Harney, J.W., Koenig, R.J., and Moore, D.D. 1989. Functional characterization of the rat growth hormone promoter elements required for induction by thyroid hormone with and without a co-transfected beta type thyroid hormone receptor. J Biol Chem. 264:178–182.PubMedGoogle Scholar
  9. 9.
    Mansen A, Yu F, Forrest D, Larsson L, Vennstrom B. 2001 TRs have common and isoform-specific functions in regulation of the cardiac myosin heavy chain genes. Mol Endocrinol 15:2106–14.PubMedCrossRefGoogle Scholar
  10. 10.
    Pazos-Moura C, Abel ED, Boers ME, Moura E, Hampton TG, Wang J, Morgan JP, Wondisford FE. Cardiac dysfunction caused by myocardial-specific expression of a mutant thyroid hormone receptor, Circ Res, 2000, 2000, 86:700–706.CrossRefGoogle Scholar
  11. 11.
    Nikodem, V.M., Magnuson, M.A., Dozin, B., and Morioka, H. 1989. Coding nucleotide sequence of rat malic enzyme mRNA and tissue specific regulation by thyroid hormone. Endocr Res. 15:547–564.PubMedCrossRefGoogle Scholar
  12. 12.
    Bodenner, D.L., Mroczynski, M.A., Weintraub, B.D., Radovick, S., and Wondisford, F.E. 1991 A detailed functional and structural analysis of a major thyroid hormone inhibitory element in the human thyrotropin beta-subunit gene. J Biol Chem. 266:21666–21673.PubMedGoogle Scholar
  13. 13.
    Hollenberg, A.N., Monden, T., Flynn, T.R., Boers, M.E., Cohen, O., and Wondisford, F.E. 1995. The human thyrotropin-releasing hormone gene is regulated by thyroid hormone through two distinct classes of negative thyroid hormone response elements.Mol Endocrinol. 9:540–550.Google Scholar
  14. 14.
    Beck-Peccoz P, Amr S, Menezes-Ferreira MM, Faglia G, Weintraub BD. 1985 Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N Engl J Med. 312:1085–90.PubMedCrossRefGoogle Scholar
  15. 15.
    Forrest, D., Erway, L.C., Ng, L., Altschuler, R., and Curran, T. 1996. Thyroid hormone receptor beta is essential for development of auditory function. Nat Genet. 13:354–357.PubMedCrossRefGoogle Scholar
  16. 16.
    Weiss, R.E., Forrest, D., Pohlenz, J., Cua, K., Curran, T., and Refetoff, S. 1997. Thyrotropin regulation by thyroid hormone in thyroid hormone receptor beta-deficient mice. Endocrinology. 138:3624–3629.PubMedCrossRefGoogle Scholar
  17. 17.
    Wikstrom L, Johansson C, Salto C, Barlow C, Campos Barros A, Baas F, Forrest D, Thoren P, Vennstrom B. 1998 Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J 17:455–61.PubMedCrossRefGoogle Scholar
  18. 18.
    Gauthier, K., Chassande, O., Plateroti, M., Roux, J.P., Legrand, C., Pain, B., Rousset, B., Weiss, R., Trouillas, J., and Samarut, J. 1999. Different functions for the thyroid hormone receptors TRalpha and TRbeta in the control of thyroid hormone production and postnatal development. EMBO J. 18:623–631.PubMedCrossRefGoogle Scholar
  19. 19.
    Abel, E.D., Boers, M.E., Pazos-Moura, C., Moura, E., Kaulbach, H., Zakaria, M., Lowell, B., Radovick, S., Liberman, M.C., and Wondisford, F.E. 1999. Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system. J Clin Invest. 104: 291–300.PubMedCrossRefGoogle Scholar
  20. 20.
    Abel ED, Ahima R, Boer M-E, Elmquist JK, Wondisford FE. 2001 Critical role for thyroid hormone receptor β-2 in the regulation of TRH neurons in the paraventricular hypothalamus. J Clin Invest 107:1017–10232.PubMedCrossRefGoogle Scholar
  21. 21.
    Gothe, S., Wang, Z., Ng, L., Kindblom, J.M., Barros, A.C., Ohlsson, C., Vennstrom, B., and Forrest, D. 1999. Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev. 13:1329–1341.PubMedCrossRefGoogle Scholar
  22. 22.
    Abel ED, Kaulbach HC, Boers ME, Campos-Barros A, Hashimoto K, Forrest D, Wondisford FE. 1999 Elucidation of the pathophysiology of central resistance to thyroid hormone by pituitary expression of a mutant thyroid hormone receptor in transgenic mice. J Clin Invest 103:271–279.PubMedCrossRefGoogle Scholar
  23. 23.
    Abel ED, Moura EG, Ahima RS, Campo-Barros A, Pazos-Moura CC, Boers M-E, Kaulbach HC, Forrest D, Wondisford FE. 2003 Dominant Inhibition of thyroid hormone action selectively in the pituitary of TR-β null mice abolishes the regulation of thyrotropin by thyroid hormone. Mol Endocrinol (in press).Google Scholar
  24. 24.
    Refetoff, S., Weiss, R.E., and Usala, S.J. 1993. The syndromes of resistance to thyroid hormone. Endocr Rev. 14:348–399.PubMedGoogle Scholar
  25. 25.
    Usala SJ, Menke JB, Watson TL, Wondisford FE, Weintraub BD, Berard J, Bradley WEC, Ono S, Mueller OT, Bercu BB. A homozygous deletion in the c-erbA-β thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: Isolation and characterization of the mutant receptor. Mol Endocrinol, 1991; 5:327–335.PubMedCrossRefGoogle Scholar
  26. 26.
    Safer J, Cohen RN, Hollenberg AN, Wondisford FE. 1998 Defective release of nuclear corepressors by hinge mutants of the thyroid hormone: mechanism of resistance to thyroid hormone, J Biol Chem 273:30175–30182PubMedCrossRefGoogle Scholar
  27. 27.
    Hashimoto, K., Curty, F.H., Borges, P.P., Lee, C.E., Abel, E.D., Elmquist, J.K., Cohen, R.N., and Wondisford, F.E. 2001. An unliganded thyroid hormone receptor causes severe neurological dysfunction. Proc Natl Acad Sci USA. 98:3998–4003.PubMedCrossRefGoogle Scholar
  28. 28.
    Oppenheimer, J.H., and Schwartz, H.L. 1997. Molecular basis of thyroid hormonedependent brain development. Endocr Rev. 18:462–475.PubMedCrossRefGoogle Scholar
  29. 29.
    Koibuchi, N., and Chin, W.W. 2000.Thyroid hormone action and brain development. Trends Endocrinol Metab. 11:123–128.PubMedCrossRefGoogle Scholar
  30. 30.
    Morte, B., Manzano, J., Scanlan, T., Vennstrom, B., and Bernal, J. 2002. Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism. Proc Natl Acad Sci USA. 99:3985–3989.PubMedCrossRefGoogle Scholar
  31. 31.
    Reichardt, H.M., Kaestner, K.H., Tuckermann, J., Kretz, O., Wessely, O., Bock, R., Gass, P., Schmid, W., Herrlich, P., Angel, P., and Schutz, G. 1998. DNA binding of the glucocorticoid receptor is not essential for survival. Cell. 93:531–541.PubMedCrossRefGoogle Scholar
  32. 32.
    Shibusawa, N., Hollenberg, A.N., and Wondisford, F.E. 2003. Thyroid hormone receptor DNA binding is required for both positive and negative gene regulation. J Biol Chem. 278:732–738.PubMedCrossRefGoogle Scholar
  33. 33.
    Bunting, M., Bernstein, K.E., Greer, J.M., Capecchi, M.R., and Thomas, K.R. 1999. Targeting genes for self-excision in the germ line. Genes Dev. 13:1524–1528.PubMedCrossRefGoogle Scholar
  34. 34.
    Shibusawa N, Hashimoto K, Nikrodhanond AA, Liberman MC, Applebury ML, Liao XH, Robbins JT, Refetoff S, Cohen RN, Wondisford FE 2003 Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo J Clin Invest (in press).Google Scholar
  35. 35.
    Tagami, T., Madison, L.D., Nagaya, T., and Jameson, J.L. 1997. Nuclear receptor corepressors activate rather than suppress basal transcription of genes that are negatively regulated by thyroid hormone. Mol Cell Biol. 17:2642–2648.PubMedGoogle Scholar
  36. 36.
    Tagami, T., Park, Y., and Jameson, J.L. 1999. Mechanisms that mediate negative regulation of the thyroid-stimulating hormone alpha gene by the thyroid hormone receptor. J Biol Chem. 274:22345–22353.PubMedCrossRefGoogle Scholar
  37. 37.
    Ng, L., Hurley, J.B., Dierks, B., Srinivas, M., Salto, C., Vennstrom, B., Reh, T.A., and Forrest, D. 2001. A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nat Genet. 27:94–98.PubMedGoogle Scholar
  38. 38.
    Deol, M.S. 1976. The role of thyroxine in the differentiation of the organ of Corti.Acta Otolaryngol. 81:429–435.Google Scholar
  39. 39.
    Rusch, A., Erway, L.C., Oliver, D., Vennstrom, B., and Forrest, D. 1998. Thyroid hormone receptor beta-dependent expression of a potassium conductance in inner hair cells at the onset of hearing. Proc Natl Acad Sci U S A. 95:15758–15762.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Fredric E. Wondisford
    • 1
  1. 1.Section of Endocrinology, Department of MedicineUniversity of ChicagoUSA

Personalised recommendations