Ablation of TR (cid:1) 2 and a Concomitant Overexpression of (cid:1) 1 Yields a Mixed Hypo- and Hyperthyroid Phenotype in Mice

Thyroid hormone governs a diverse repertoire of physiological functions through receptors encoded in the receptor genes (cid:1) and (cid:2) , which each generate variant proteins. In mammals, the (cid:1) gene generates, in addition to the normal receptor TR (cid:1) 1, a non-hormone-binding variant TR (cid:1) 2 whose exact function is unclear. Here, we present the phenotype associated with the targeted ablation of TR (cid:1) 2 expression. Selective ablation of TR (cid:1) 2 resulted in an inevitable, concomitant overexpression of TR (cid:1) 1. Both TR (cid:1) 2 (cid:3) / (cid:4) and (cid:4) / (cid:4) mice show a complex phenotype with low levels of free T 3 and free T 4 , and have inappropriately normal levels of TSH. The thyroid glands exhibit mild morphological signs of dysfunction and respond poorly to TSH, suggesting that the genetic changes affect the ability of the gland to release thyroid hormones. However,

[1]  W. Giles,et al.  Cardiac Ion Channel Expression and Contractile Function in Mice with Deletion of Thyroid Hormone Receptor α or β1 , 2001 .

[2]  P. Macchia,et al.  Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor alpha. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[3]  T. Hökfelt,et al.  Expression of peptides and other neurochemical markers in hypothalamus and olfactory bulb of mice devoid of all known thyroid hormone receptors , 2000, Neuroscience.

[4]  J. Gustafsson,et al.  Obesity and Disturbed Lipoprotein Profile in Estrogen Receptor-α-Deficient Male Mice , 2000 .

[5]  K. Takano,et al.  Serum leptin levels and bioelectrical impedance assessment of body composition in patients with Graves' disease and hypothyroidism. , 1999, Endocrine journal.

[6]  J. Gustafsson,et al.  Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice. , 1999, The Journal of clinical investigation.

[7]  D. Forrest,et al.  Cardiovascular phenotype and temperature control in mice lacking thyroid hormone receptor-β or both α1 and β. , 1999, American journal of physiology. Heart and circulatory physiology.

[8]  D. Forrest,et al.  Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. , 1999, Genes & development.

[9]  J. Samarut,et al.  Different functions for the thyroid hormone receptors TRα and TRβ in the control of thyroid hormone production and post‐natal development , 1999 .

[10]  D. Forrest,et al.  Thyroid hormone receptor beta-dependent expression of a potassium conductance in inner hair cells at the onset of hearing. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  P. Chambon,et al.  Absence of thyroid hormone receptor β–retinoid X receptor interactions in auditory function and in the pituitary–thyroid axis , 1998, Neuroreport.

[12]  P. Kopp,et al.  The Thyroid Hormone Receptor Variant α2 Is a Weak Antagonist because It Is Deficient in Interactions with Nuclear Receptor Corepressors. , 1998, Endocrinology.

[13]  C. Ohlsson,et al.  Growth hormone and bone. , 1998, Endocrine reviews.

[14]  Frank Baas,et al.  Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor α1 , 1998, The EMBO journal.

[15]  M. Taketo,et al.  Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[16]  C. Dehay,et al.  The T3Rα gene encoding a thyroid hormone receptor is essential for post‐natal development and thyroid hormone production , 1997, The EMBO journal.

[17]  P. Thorén,et al.  The effects of triiodothyronine (T3) on heart rate, temperature and ECG measured with telemetry in freely moving mice. , 1997, Acta physiologica Scandinavica.

[18]  D. Forrest,et al.  Thyroid hormone receptor β is essential for development of auditory function , 1996, Nature Genetics.

[19]  D. Forrest,et al.  Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue‐specific modulation of receptor function. , 1996, The EMBO journal.

[20]  W. Dillmann.  Editorial: thyroid hormone action and cardiac contractility - a complex affair. , 1996, Endocrinology.

[21]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

[22]  M. Lazar,et al.  Functional regulation of thyroid hormone receptor variant TR alpha 2 by phosphorylation , 1995, Molecular and cellular biology.

[23]  T. Miyamoto,et al.  The dominant negative effect of thyroid hormone receptor splicing variant alpha 2 does not require binding to a thyroid response element. , 1995, Molecular endocrinology.

[24]  F. Epstein,et al.  The molecular basis of thyroid hormone action. , 1994, The New England journal of medicine.

[25]  B. Breier,et al.  Radioimmunoassays for IGFs and IGFBPs. , 1994, Growth regulation.

[26]  M. Lazar,et al.  Dominant negative activity of an endogenous thyroid hormone receptor variant (alpha 2) is due to competition for binding sites on target genes. , 1993, The Journal of biological chemistry.

[27]  J. Tata.  Early amphibian pattern formation Utrecht, 12–26 September 1993 , 1993, Mechanisms of Development.

[28]  C. Ohlsson,et al.  Effects of tri-iodothyronine and insulin-like growth factor-I (IGF-I) on alkaline phosphatase activity, [3H]thymidine incorporation and IGF-I receptor mRNA in cultured rat epiphyseal chondrocytes. , 1992, The Journal of endocrinology.

[29]  M. Lazar,et al.  The unique C-termini of the thyroid hormone receptor variant, c-erbA alpha 2, and thyroid hormone receptor alpha 1 mediate different DNA-binding and heterodimerization properties. , 1992, Molecular endocrinology.

[30]  V. Laudet,et al.  Genomic organization of the human thyroid hormone receptor α (c-erbA-1) gene , 1991 .

[31]  Y. Yaoita.  Xenopus laevis α and β thyroid hormone receptors , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[32]  K. Strait,et al.  Relationship of c-erbA mRNA content to tissue triiodothyronine nuclear binding capacity and function in developing and adult rats. , 1990, The Journal of biological chemistry.

[33]  D. Forrest,et al.  Requirement for the C-terminal domain of the v-erbA oncogene protein for biological function and transcriptional repression. , 1990, Oncogene.

[34]  T. Mitsuhashi,et al.  Regulation of expression of the alternative mRNAs of the rat alpha-thyroid hormone receptor gene. , 1989, The Journal of biological chemistry.

[35]  Nobuyuki Miyajima,et al.  Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus , 1989, Cell.

[36]  M. Lazar,et al.  A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit , 1989, Molecular and cellular biology.

[37]  P. Larsen,et al.  Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing , 1989, Nature.

[38]  L. Degroot,et al.  Expression of three forms of thyroid hormone receptor in human tissues. , 1989, Molecular endocrinology.

[39]  M. Lazar,et al.  Identification of a rat c-erbA alpha-related protein which binds deoxyribonucleic acid but does not bind thyroid hormone. , 1988, Molecular endocrinology.

[40]  H. Freake,et al.  Triiodothyronine nuclear binding capacity in rat tissues correlates with a 6.0 kilobase (kb) and not a 2.6 kb messenger ribonucleic acid hybridization signal generated by a human c-erbA probe. , 1988, Molecular endocrinology.

[41]  T. Mitsuhashi,et al.  Alternative splicing generates messages encoding rat c-erbA proteins that do not bind thyroid hormone. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[42]  R. Evans,et al.  The c-erb-A gene encodes a thyroid hormone receptor , 1986, Nature.

[43]  H. Beug,et al.  The c-erb-A protein is a high-affinity receptor for thyroid hormone , 1986, Nature.

[44]  J. Bishop,et al.  Isolation and characterization of chicken DNA homologous to the two putative oncogenes of avian erythroblastosis virus , 1982, Cell.

[45]  Choh Hao Li,et al.  The effects of chronic administration of thyroxin to hypophysectomized rats on their skeletal growth, maturation and response to growth hormone , 1954, The Anatomical record.

[46]  R. D. Ray,et al.  Growth and differentiation of the skeleton in thyroidectomized-hypophysectomized rats treated with thyroxin, growth hormone, and combination. , 1954, The Journal of bone and joint surgery. American volume.