Skip to main content
Log in

Action of thyroid hormone in brain

  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Among the most critical actions of thyroid hormone in man and other mammals are those exerted on brain development. Severe hypothyroidism during the neonatal period leads to structural alterations, including hypomyelination and defects of cell migration and differentiation, with long-lasting, irreversible effects on behavior and performance. A complex regulatory mechanism operates in brain involving regulation of the concentration of the active hormone, T3, and the control of gene expression. Most brain T3 is formed locally from its precursor, T4, by the action of type II deiodinase which is expressed in glial cells, tanycytes, and astrocytes. Type III deiodinase (DIII) is also involved in the regulation of T3 concentrations, especially during the embryonic and early post-natal periods. DIII is expressed in neurons and degrades T4 and T3 to inactive metabolites. The action of T3 is mediated through nuclear receptors, which are expressed mainly in neurons. The receptors are ligand-modulated transcription factors, and a number of genes have been identified as regulated by thyroid hormone in brain. The regulated genes encode proteins of myelin, mitochondria, neurotrophins and their receptors, cytoskeleton, transcription factors, splicing regulators, cell matrix proteins, adhesion molecules, and proteins involved in intracellular signaling pathways. The role of thyroid hormone is to accelerate changes of gene expression that take place during development. Surprisingly, null-mutant mice for the T3 receptors show almost no signs of central nervous system involvement, in contrast with the severe effects of hypothyroidism. The resolution of this paradox is essential to understand the role of thyroid hormone and its receptors in brain development and function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Joffe R.T., Sokolov S.T.H. Thyroid hormones, the brain, and affective disorders. Crit. Rev. Neurobiol. 1994, 8: 45–63.

    CAS  PubMed  Google Scholar 

  2. Laureno R. Neurologic manifestations of thyroid disease. Endocrinologist 1996, 6: 467–473.

    Google Scholar 

  3. Morreale de Escobar G., Escobar del Rey F., Ruiz-Marcos A. Thyroid hormone and the developing brain. In: Dussault J.H., Walker P. (Eds.), Congenital hypothyroidism. Marcel Decker, Inc., New York 1983, pp 85–126.

    Google Scholar 

  4. Bernal J., Nunez J. Thyroid hormones and brain development. Eur. J. Endocrinol. 1995, 133: 390–398.

    CAS  PubMed  Google Scholar 

  5. Bernal J., Guadaño-Ferraz A. Thyroid hormone and the development of the brain. Curr. Opin. Endocrinol. Diabetes 1998, 5: 296–302.

    CAS  Google Scholar 

  6. Muñoz A., Bernal J. Biological activities of thyroid hormone receptors. Eur. J. Endocrinol. 1997, 137: 433–445.

    PubMed  Google Scholar 

  7. Legrand J. Effects of thyroid hormones on central nervous system. In: Yanai J. (Ed.), Neurobehavioral teratology. Elsevier Science Publishers, Amsterdam, 1984, 331–363.

    Google Scholar 

  8. Oppenheimer J.H., Schwartz, H.L. Molecular Basis of thyroid hormone-dependent brain development. Endocr. Rev. 1997, 18: 462–475.

    CAS  PubMed  Google Scholar 

  9. Porterfield S.P., Hendrich C.E. The role of thyroid hormones in prenatal and neonatal neurological development-current perspectives. Endocr. Rev. 1993, 14: 94–106.

    CAS  PubMed  Google Scholar 

  10. Hollowell J.G. Jr., Hannon, W.H. Teratogen update: iodine deficiency, a community teratogen. Teratology 1997, 55: 389–405.

    CAS  PubMed  Google Scholar 

  11. Morreale de Escobar G., Obregón, M.J., Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism, or to maternal hypothyroxinemia? J. Clin. Endocrinol. Metabol. 2000, 85: 3975–3987.

    CAS  Google Scholar 

  12. Marin-Padilla M. Three-dimensional structural organization of layer I of the human cerebral cortex: a Golgi study. J. Comp. Neurol. 1990, 299: 89–105.

    CAS  PubMed  Google Scholar 

  13. García-Fernández L.F., Rausell E., Urade Y., Hayaishi O., Bernal J. Muñoz A. Hypothyroidism alters the expression of prostaglandin D2 synthase/beta trace in specific areas of the developing rat brain. Eur. J. Neurosci. 1997, 9: 1566–1573.

    PubMed  Google Scholar 

  14. Alvarez-Dolado M., Ruiz M., del Rio J.A., Alcantara S., Burgaya F., Sheldon M., Nakajima K., Bernal J., Howell B.W., Curran T., Soriano E. Muñoz A. Thyroid hormone regulates reelin and dab1 expression during brain development. J. Neurosci. 1999, 19: 6979–6973.

    CAS  PubMed  Google Scholar 

  15. Gleeson J.G., Walsh C.A. Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends Neurosci. 2000, 23: 352–359.

    CAS  PubMed  Google Scholar 

  16. Gravel C., Hawkes R. Maturation of the corpus callosum of the rat: I. Influence of thyroid hormones on the topography of callosal projections. J. Comp. Neurol. 1990, 291: 128–146.

    CAS  PubMed  Google Scholar 

  17. Berbel P., Guadano-Ferraz A., Martinez M., Quiles J.A., Balboa R. Innocenti G.M. Organization of auditory callosal connections in hypothyroid adult rats. Eur. J. Neurosci. 1993, 5: 1465–1478.

    CAS  PubMed  Google Scholar 

  18. Lucio R.A., Garcia J.V., Ramon Cerezo J., Pacheco P., Innocenti G.M., Berbel P. The development of auditory callosal connections in normal and hypothyroid rats. Cereb. Cortex 1997, 7: 303–316.

    CAS  PubMed  Google Scholar 

  19. Gould E., Butcher L.L. Developing cholinergic basal forebrain neurons are sensitive to thyroid hormone. J. Neurosci. 1989, 9: 3347–3358.

    CAS  PubMed  Google Scholar 

  20. Gravel C., Sasseville R., Hawkes, R. Maturation of the corpus callosum of the rat: II. Influence of thyroid hormones on the number and maturation of axons. J. Comp. Neurol. 1990, 291: 147–161.

    CAS  PubMed  Google Scholar 

  21. Legrand J. Analyse de l’action morphogénétic des hormones thyroïdiennes sur le cervelet du jeune rat. Arch. Anat. Microsc. Morphol. Exp. 1967, 56: 205–244.

    CAS  PubMed  Google Scholar 

  22. Ruiz-Marcos A., Sanchez-Toscano F., Obregón M.J., Escobar del Rey F., Morreale de Escobar G. Reversible morphological alterations of cortical neurons in juvenile and adult hypothyroidism in the rat. Brain Res. 1980, 185: 91–102.

    CAS  PubMed  Google Scholar 

  23. Ruiz-Marcos A., Sanchez-Toscano F., Obregón M.J., Escobar del Rey F., Morreale de Escobar G. Thyroxine treatment and recovery of hypothyroidism-induced pyramidal cell damage. Brain Res. 1982, 239: 559–574.

    CAS  PubMed  Google Scholar 

  24. Gould E., Allan M.D., McEwen B.S. Dendritic spine density of adult hippocampal pyramidal cells is sensitive to thyroid hormone. Brain Res. 1990, 525: 327–329.

    CAS  PubMed  Google Scholar 

  25. Ruiz-Marcos A., Cartagena P., García A., Escobar del Rey F., Morreale de Escobar G. Rapid effects of adult-onset hypothyroidism on dendritic spines of pyramidal cells of the rat cerebral cortex. Exp. Brain Res. 1988, 73: 583–588.

    CAS  PubMed  Google Scholar 

  26. Balazs R., Brooksbank B.W.L., Davison A.N., Eayrs J.T., Wilson D.A. The effect of neonatal thyroidectomy on myelination in the rat brain. Brain Res. 1969, 15: 219–232.

    CAS  PubMed  Google Scholar 

  27. Adamo A.M., Aloise P.A., Soto E.F., Pasquini, J.M. Neonatal hyperthyroidism in the rat produces an increase in the activity of microperoxisomal marker enzymes coincident with biochemical signs of accelerated myelination. J. Neurosci. Res. 1990, 25: 353–359.

    CAS  PubMed  Google Scholar 

  28. Berbel P., Guadaño-Ferraz A., Angulo A., Cerezo J.R. Role of thyroid hormones in the maturation of interhemispheric connections in rat. Behav. Brain Res. 1994, 64: 9–14.

    CAS  PubMed  Google Scholar 

  29. Notterpek L.M., Rome L.H. Functional evidence for the role of axolemma in CNS myelination. Neuron 1994, 13: 473–485.

    CAS  PubMed  Google Scholar 

  30. Izumo S., Mahdavi V. Thyroid hormone receptor alpha isoforms generated by alternative splicing differentially activate myosin HC gene transcription. Nature 1988, 334: 539–542.

    CAS  PubMed  Google Scholar 

  31. Lazar M.A., Hodin R.A., Chin W.W. Human carboxyl-terminal variant of a-type c-erbA inhibits trans-activation by thyroid hormone receptors without binding thyroid hormone. Proc. Natl. Acad. Sci. USA 1989, 86: 7771–7774.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Koenig R.J., Lazar M.A., Hodin R.A., Brent G.A., Larsen P.R., Chin W.W., Moore D.D. Inhibition of thyroid hormone action by a non-hormone binding c-erba protein generated by alternative mRNA splicing. Nature 1989, 337: 659–661.

    CAS  PubMed  Google Scholar 

  33. Lazar M.A., Hodin R.A., Darling D.S., Chin W.W. A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit. Mol. Cell. Biol. 1989, 9: 1128–1136.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Miyajima N., Horiuchi R., Shibuya Y., Fukushige S., Matsubara K., Toyoshima K., Yamamoto T. Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus. Cell 1989, 57: 31–39.

    CAS  PubMed  Google Scholar 

  35. Chomez P., Neveu I., Mansen A., Kiesler E., Larsson L., Vennstrom B., Arenas E. Increased cell death and delayed development in the cerebellum of mice lacking the rev-erbA (alpha) orphan receptor. Development 2000, 127: 1489–498.

    CAS  PubMed  Google Scholar 

  36. Chassande O., Fraichard A., Gauthier K., Flamant F., Legrand C., Savatier P., Laudet V., Samarut J. Identification of transcripts initiated from an internal promoter in the c-erbA alpha locus that encode inhibitors of retinoic acid receptor-alpha and triiodothyronine receptor activities. Mol. Endocrinol. 1997, 11: 1278–1290.

    CAS  PubMed  Google Scholar 

  37. Williams G.R. Cloning and characterization of two novel thyroid hormone receptor beta isoforms. Mol. Cell Biol. 2000, 20: 8329–8342.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Sap J., Muñoz A., Schmitt J., Stunnenberg H., Vennström B. Repression of transcription mediated at a thyroid hormone response element by the v-erbA oncogene product. Nature 1989, 340: 242–244.

    CAS  PubMed  Google Scholar 

  39. Yang Z., Hong S.H., Privalsky M.L. Transcriptional anti-repression. Thyroid hormone receptor beta-2 recruits SMRT corepressor but interferes with subsequent assembly of a functional corepressor complex. J. Biol. Chem. 1999, 274: 37131–37138.

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Oberste-Berghaus C., Zanger K., Hashimoto K., Cohen R.N., Hollenberg A.N., Wondisford F.E. Thyroid hormone-independent interaction between the thyroid hormone receptor beta2 amino terminus and coactivators. J. Biol. Chem. 2000, 275: 1787–1792.

    CAS  PubMed  Google Scholar 

  41. Pérez-Castillo A., Bernal J., Ferreiro B., Pans T. The early ontogenesis of thyroid hormone receptor in the rat fetus. Endocrinology 1985, 117: 2457–2461.

    PubMed  Google Scholar 

  42. Schwartz H.L., Oppenheimer J.H. Ontogenesis of 3,5,3′-triiodothyronine receptors in neonatal rat brain, dissociation between receptor concentration and stimulation of oxygen consumption by 3,5,3′-triiodothyronine. Endocrinology 1978, 103: 943–948.

    CAS  PubMed  Google Scholar 

  43. Strait K.A., Schwartz H.L., Perezcastillo A., Oppenheimer J.H. Relationship of C-erbA messenger RNA content to tissue triiodothyronine nuclear binding capacity and function in developing and adult rats. J. Biol. Chem. 1990, 265: 10514–10521.

    CAS  PubMed  Google Scholar 

  44. Ferreiro B., Pastor R., Bernal J. T3 receptor occupancy and T3 levels in plasma and cytosol during rat brain development. Acta Endocrinol. (Copenh.) 1990, 123: 95–99.

    CAS  Google Scholar 

  45. Bernal J., Pekonen F. Ontogenesis of the nuclear 3,5,3′-triiodothyronine receptor in the human fetal brain. Endocrinology 1984, 114: 677–679.

    CAS  PubMed  Google Scholar 

  46. Iskaros J., Pickard M., Evans I., Sinha A., Hardiman P., Ekins R. Thyroid hormone receptor gene expression in first trimester human fetal brain. J. Clin. Endocrinol. Metabol. 2000, 85: 2620–2623.

    CAS  Google Scholar 

  47. Dobbing J., Sands J. Timing of neuroblast multiplication in developing human brain. Nature 1970, 226: 639–640.

    CAS  PubMed  Google Scholar 

  48. Ferreiro B., Bernal J., Goodyer C.G., Branchard C.L. Estimation of nuclear thyroid hormone receptor saturation in human fetal brain and lung during early gestation. J. Clin. Endocrinol. Metabol. 1988, 67: 853–856.

    CAS  Google Scholar 

  49. Burrow G.N., Fisher D.A., Larsen P.R. Maternal and fetal thyroid function. N. Engl. J. Med. 1994, 331: 1072–1078.

    CAS  PubMed  Google Scholar 

  50. Darras V.M., Hume R., Visser T.J. 51. Regulation of thyroid hormone metabolism during fetal development. Mol. Cell. Endocrinol. 1999, 25: 37–47.

    Google Scholar 

  51. Richard K., Hume R., Kaptein E., Sanders J.P., van Toor H., de Herder W.W., den Hollander J.C., Krenning E.P., Visser T.H. Ontogeny of iodothyronine deiodinases in human liver. J. Clin. Endocrinol. Metabol. 1998, 83: 2868–2874.

    CAS  Google Scholar 

  52. Croteau W., Davey J.C., Galton V.A., St. Germain D.L. Cloning of the mammalian type II iodothyronine deiodinase: a selenoprotein differentially expressed and regulated in the human brain and other tissues. J. Clin. Invest. 1996, 98: 405–417.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Dowling A.L., Iannacone E.A., Zoeller R.T. Maternal hypothyroidism selectively affects the expression of neuroendocrine-specific protein a messenger ribonucleic acid in the proliferative zone of the fetal rat brain cortex. Endocrinology 2001, 142: 390–399.

    CAS  PubMed  Google Scholar 

  54. Bradley D.J., Towle H.C., Young W.S. Spatial and temporal expression of α- and β- thyroid hormone receptor mRNAs, including the β2-subtype, in the developing mammalian nervous system. J. Neurosci. 1992, 12: 2288–2302.

    CAS  PubMed  Google Scholar 

  55. Forrest D., Hallbook F., Persson H., Vennstrom B. Distinct functions for thyroid hormone receptors-alpha and receptor-beta in brain development indicated by differential expression of receptor genes. EMBO J. 1991, 10: 269–275.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Mellström B., Naranjo J.R., Santos A., González A.M., Bernal J. Independent expression of the α and β c-erbA genes in developing rat brain. Mol. Endocrinol. 1991, 5: 1339–1350.

    PubMed  Google Scholar 

  57. Lechan R.M., Qi Y., Berrodin T.J., Davis K.D., Schwartz H.L., Strait K.A., Oppenheimer J.H., Lazar M.A. Immunocytochemical delineation of thyroid hormone receptor b2-like immunoreactivity in the rat central nervous system. Endocrinology 1993, 132: 2461–2469.

    CAS  PubMed  Google Scholar 

  58. Luo M., Faure R. Dussault J.H. Ontogenesis of nuclear T3 receptors in primary cultured astrocytes and neurons. Brain Res. 1986, 381: 275–280.

    CAS  PubMed  Google Scholar 

  59. Yusta B., Besnard F., Ortiz-Caro J., Pascual A., Aranda A., Sarlieve L. Evidence for the presence of nuclear 3,5,3′-triiodothyronine receptors in secondary cultures of pure rat oligodendrocytes. Endocrinology 1988, 122: 2278–2284.

    CAS  PubMed  Google Scholar 

  60. Carlson D.J., Strait K.A., Schwartz H.L., Oppenheimer J.H. Immunofluorescent localization of thyroid hormone receptor isoforms in glial cells of rat brain. Endocrinology 1994, 135: 1831–1836.

    CAS  PubMed  Google Scholar 

  61. Kolodny J.M., Leonard J.L., Larsen P.R., Silva J.E. Studies of nuclear 3,5,3′-triiodothyronine binding in primary cultures of rat brain. Endocrinology 1985, 117: 1848–1857.

    CAS  PubMed  Google Scholar 

  62. Leonard J.L., Farwell A.P., Yen P.M., Chin W.W., Stula M. Differential expression of thyroid hormone receptor isoforms in neurons and astroglial cells. Endocrinology 1994, 135: 548–555.

    CAS  PubMed  Google Scholar 

  63. Nataf B., Sfez M. Debt du fonctionnement de la thyroide foetale du rat. Soc. Biol. 1961, 156: 1235–1238.

    Google Scholar 

  64. Woods R.J., Sinha A.K., Ekins R.P. Uptake and metabolism of thyroid hormones by the rat foetus early in pregnancy. Clin. Sci. (Colch.) 1984, 67: 359–363.

    CAS  Google Scholar 

  65. Obregón M.J., Mallol J., Pastor R., Morreale de Escobar G., Escobar del Rey G. L-thyroxine and 3,3′,5-triiodo-L-thyronine in rat embryos before onset of fetal thyroid function. Endocrinology 1984, 114: 305–307.

    PubMed  Google Scholar 

  66. Morreale de Escobar G., Pastor R., Obregón M.J., Escobar del Rey F. Effects of maternal hypothyroidism on the weight and thyroid hormone content of rat embryonic tissues. Endocrinology 1985, 117: 1890–1901.

    CAS  PubMed  Google Scholar 

  67. Morreale de Escobar G., Obregón M.J., Escobar del Rey F. Fetal and maternal thyroid hormones. Horm. Res. 1987, 26: 12–27.

    CAS  PubMed  Google Scholar 

  68. Porterfield S.P., Hendrich C.E. Tissue iodothyronine levels in fetuses of control and hypothyroid rats at 13 and 16 days gestation. Endocrinology 1992, 131: 195–200.

    CAS  PubMed  Google Scholar 

  69. Morreale de Escobar G., Calvo R., Obregón M.J., Escobar del Rey F. Contribution of maternal thyroxine to fetal thyroxine pools in normal rats near term. Endocrinology 1990, 126: 2765–2767.

    CAS  PubMed  Google Scholar 

  70. Myant N.B. Passage of thyroxine and tri-iodothyronine from mother to fetus in pregnant women. Clin. Sci. (Colch.) 1958, 17: 75–79.

    CAS  Google Scholar 

  71. Grümbach M.M., Werner S.C. Transfer of thyroid hormone across the human placenta at term. J. Clin. Endocrinol. Metab. 1956, 16: 1392–1395.

    PubMed  Google Scholar 

  72. Vulsma T., Gons M.H., de Vijlder J. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid dysgenesis. N. Engl. J. Med. 1989, 321: 13–16.

    CAS  PubMed  Google Scholar 

  73. Contempré B., Jauniaux E., Calvo R., Jurkovic D., Campbell S., Morreale de Escobar G. Detection of thyroid hormones in human embryonic cavities during the first trimester of pregnancy. J. Clin. Endocrinol. Metabol. 1993, 77: 1719–1722.

    Google Scholar 

  74. Laterra J., Goldstein G.W. Ventricular organization of cerebrospinal fluid: blood-brain barrier, brain edema and hydrocephalus. In: Kandel E.R., Schwartz J.M., Jessell J.H., (Eds.), Principles of neural science. McGraw-Hill, New York, 2000, p. 1288–1301.

    Google Scholar 

  75. Chanoine J.-P., Alex S., Fang S.L., Stone S., Leonard J.L., Köhrle J., Braverman L.E. Role of transthyretin in the transport of thyroxine from the blood to the choroid plexus, the cerebrospinal fluid, and the brain. Endocrinology 1992, 130: 933–938.

    CAS  PubMed  Google Scholar 

  76. Kendall J.W., Jacobs J.J., Kramer R.M. Studies on the transport of hormones from the cerebrospinal fluid to hypothalamus and pituitary. In: Knigge K.M., Scott D.E., Weindl A. Brain-endocrine interaction. Median eminence: structure and function. 1972 Karger, Basel, 1971, p. 342–349.

    Google Scholar 

  77. Dratman M.B., Crutchfield F.L., Schoenhoff M.B. Transport of iodothyronines from bloodstream to brain: contributions by blood:brain and choroid plexus:cerebrospinal fluid barriers. Brain Res. 1991, 554: 229–236.

    CAS  PubMed  Google Scholar 

  78. Dickson P.W., Aldred A.R., Menting J.G.T., Marley P.D., Sawyer W.H., Schreiber G. Thyroxine transport in choroid plexus. J. Biol. Chem. 1987, 262: 13907–13915.

    CAS  PubMed  Google Scholar 

  79. Schreiber G., Southwell B.R., Richardson S.J. Hormone delivery systems to the brain-transthyretin. Exp. Clin. Endocrinol. Diabetes 1995, 103: 75–80.

    CAS  PubMed  Google Scholar 

  80. Southwell B.R., Duan W., Alcorn D.C.B., Richardson S.J., Kohrle J., Schreiber G. Thyroxine transport to the brain: role of protein synthesis by the choroid plexus. Endocrinology 1993, 133: 2116–2126.

    CAS  PubMed  Google Scholar 

  81. Palha J.A., Episkopou V., Maeda S., Shimada K., Gottesman M.E. Thyroid hormone metabolism in a transthyretin-null mouse strain. J. Biol. Chem. 1994, 269: 33135–33139.

    CAS  PubMed  Google Scholar 

  82. Palha J.A., Hays M.T., Morreale de Escobar G., Episkopou V., Gottesman M.E., Saraiva M.J. Transthyretin is not essential for thyroxine to reach the brain and other tissues in transthyretin-null mice. Am. J. Physiol. 1997, 272: E485–493.

    CAS  PubMed  Google Scholar 

  83. Larsen P.R., Silva J.R., Kaplan M.M. Relationships between circulating and intracellular thyroid hormones. Physiological and clinical implications. Endocr. Rev. 1981, 2: 87–102.

    CAS  PubMed  Google Scholar 

  84. van Doorn J., Roelfsema F., van der Heide D. Contribution from local conversion of thyroxine to 3,5,3′-triiodothyronine to intracellular 3,5,3′-triiodothyronine in several organs in hypothyroid rats at isotope equilibrium. Acta Endocrinol. (Copenh.) 1982, 101: 386–396.

    Google Scholar 

  85. Crantz F.R., Silva J.E., Larsen P.R. An analysis of the sources and quantity of 3,5,3′-triiodothyronine specifically bound to nuclear receptors in rat cerebral cortex and cerebellum. Endocrinology 1982, 110: 367–375.

    CAS  PubMed  Google Scholar 

  86. St Germain D.L., Galton V.A. The deiodinase family of selenoproteins. Thyroid 1997, 7: 655–668.

    Google Scholar 

  87. Leonard J.L., Visser T.J. Biochemistry and deiodination. In: Hennemann G. (Ed.), Thyroid hormone metabolism. Marcel Dekker Inc., New York, 1986, pp. 189–229.

    Google Scholar 

  88. Larsen P.R., Davis T.F., Hay I.D. The Thyroid Gland. In: Wilson J.D., Foster D.W., Kronenberg H.M., Larsen P.R. (Eds.), Williams textbook of endocrinology. W.B. Saunders & Co, Philadelphia, 1998, pp. 389–515.

    Google Scholar 

  89. Buettner C., Harney J.W., Larsen P.R. The 3′-untranslated region of human type 2 iodothyronine deiodinase mRNA contains a functional selenocysteine insertion sequence element. J. Clin. Invest. 1998, 273: 33374–33378.

    CAS  Google Scholar 

  90. Berry M.J., Banu L., Larsen P.R. Type I iodothyronine deiodinase is a selenocysteinecontaining enzyme. Nature 1991, 349: 438–440.

    CAS  PubMed  Google Scholar 

  91. Salvatore D., Low S.C., Berry M., Maia A.L., Herney J.W., Croteau W., St Germain D.L., Larsen P.R. Type 3 iodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme. J. Clin. Invest. 1995, 96: 2421–2430.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Davey J.C., Schneider M.J., Becker K.B., Galton V.A. Cloning of a 5.8 kb cDNA for a mouse type 2 deiodinase. Endocrinology 1999, 140: 1022–1025.

    CAS  PubMed  Google Scholar 

  93. Leonard J.L., Kaplan M.M., Visser T.J., Silva J.E., Larsen P.R. Cerebral cortex responds rapidly to thyroid hormones. Science 1981, 214: 571–573.

    CAS  PubMed  Google Scholar 

  94. Larsen P.R., Berry M.J. Nutritional and hormonal regulation of thyroid hormone deiodinases. Ann. Rev. Nutr. 1995, 15: 323–352.

    CAS  Google Scholar 

  95. Obregón M.J., Ruiz de Oña C., Calvo R., Escobar del Rey F., Morreale de Escobar G. Outer ring iodothyronine deiodinases and thyroid hormone economy: responses to iodine deficiency in the rat fetus and neonate. Endocrinology 1991, 129: 2663–2673.

    PubMed  Google Scholar 

  96. Krupnik V.E., Sharp J.D., Jiang C., Robison K., Chickering T.W., Amaravadi L., Brown D.E., Guyot D., Mays G., Leiby K., Chang B., Duong T., Goodearl A.D., Gearing D.P., Sokol S.Y., McCarthy S.A. Functional and structural diversity of the human Dickkopf gene family. Gene 1999, 238: 301–313.

    CAS  PubMed  Google Scholar 

  97. Leonard D.M., Stachelek S.J., Safran M., Farwell A.P., Kowalik T.F., Leonard, J.L. Cloning, expression, and functional characterization of the substrate binding subunit of rat type II iodothyronine 5′-deiodinase. J. Biol. Chem. 2000, 275: 25194–25201.

    CAS  PubMed  Google Scholar 

  98. Schneider M., Fiering S., St Germain D.L., Galton V.A. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary thyroid hormone resistance. Proceedings of the 12th International Thyroid Congress, October 22–28, 2000, Kyoto, Japan.

    Google Scholar 

  99. Ruiz de Oña C., Obregón M.J., Escobar del Rey F., Morreale de Escobar G. Developmental changes in rat brain 5′-deiodinase and thyroid hormones during the fetal period: the effects of fetal hypothyroidism and maternal thyroid hormones. Pediatr. Res. 1988, 24: 588–594.

    PubMed  Google Scholar 

  100. Bates J.M., St. Germain D.L., Galton V.A. Expression profiles of the three iodothyronine deiodinases D1, D2 and D3, in the developing rat. Endocrinology 1999, 140: 844–851.

    CAS  PubMed  Google Scholar 

  101. Guadaño-Ferraz A., Obregón M.J., St-Germain D., Bernal J. The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain. Proc. Natl. Acad. Sci. USA 1997, 94: 10391–10396.

    PubMed Central  PubMed  Google Scholar 

  102. Tu H.M., Kim S.W., Salvatore D., Bartha T., Legradi G., Larsen P.R., Lechan R.M. Regional distribution of type 2 thyroxine deiodinase messenger ribonucleic acid in rat hypothalamus and pituitary and its regulation by thyroid hormone. Endocrinology 1997, 138: 3359–3368.

    CAS  PubMed  Google Scholar 

  103. Rodriguez E.M., Gonzalez C.B., Delannoy L. Cellular organization of the lateral and postinfundibular regions of the median eminence in the rat. Cell Tissue Res. 1979, 201: 377–408.

    CAS  PubMed  Google Scholar 

  104. Riskind P.N., Kolodny J.M., Larsen P.R. The regional distribution of type II 5′-monodeiodinase in euthyroid and hypothyroid rats. Brain Res. 1987, 420: 194–198.

    CAS  PubMed  Google Scholar 

  105. Guadaño-Ferraz, A., Escámez M.J., Rausell E., Bernal J. Expression of type 2 iodothyronine deiodinase in hypothyroid rat brain indicates an important role of thyroid hormone in the development of specific primary sensory systems. J. Neurosci. 1999, 19: 3430–3439.

    PubMed  Google Scholar 

  106. Tsacopoulos M., Magistretti P.J. Metabolic coupling between glia and neurons. J. Neurosci. 1996, 16: 877–885.

    CAS  PubMed  Google Scholar 

  107. Campos-Barros A., Amma L.L., Faris J.S., Shailam R., Kelley M.W., Forrest D. Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing. Proc. Natl. Acad. Sci. USA 2000, 97: 1287–1292.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Bradley D.J., Towle H.C., Young W.S.I. Alpha and beta thyroid hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoform-specific transcriptional regulation in vivo. Proc. Natl. Acad. Sci. USA 1994, 91: 439–443.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Lauterman J., Ten Cate W.-J.F. Postnatal expression of the rat alpha-thyroid hormone receptor in the rat cochlea. Hearing Res. 1997, 107: 23–28.

    Google Scholar 

  110. Kaplan M.M., Yaskoski K.A. Maturational patterns of iodothyronine phenolic and tyrosyl ring deiodinase activities in rat cerebrum, cerebellum, and hypothalamus. J. Clin. Invest. 1981, 67: 1208–1214.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Schröder-van der Elst J.P., Van der Heide D., Morreale de Escobar G., Obregón M.J. Iodothyronine deiodinase activities in fetal rat tissues at several levels of iodine deficiency: a role for the skin in 3,5,3′-triiodothyronine economy? Endocrinology 1998, 139: 2229–2234.

    PubMed  Google Scholar 

  112. Kaplan M.M., Shaw E.A. Type II iodothyronine 5′-deiodination by human and rat placenta in vitro. J. Clin. Endocrinol. Metabol. 1984, 59: 253–257.

    CAS  Google Scholar 

  113. Koopdonk-Kool J.M., De Vijlder J.J.J., Veenboer G.J.M., Ris-Stalpers C., Kok J.H., Vulsma T., Boer, K., Visser T.J. Type II and type III deiodinase activity in human placenta as a function of gestational age. J. Clin. Endocrinol. Metabol. 1996, 81: 2154–2158.

    CAS  Google Scholar 

  114. Courtin F., Liva P., Gavaret J.M., Toru Delbauffe D., Pierre M. Induction of 5-deiodinase activity in astroglial cells by 12-O-tetradecanoylphorbol 13-acetate and fibroblast growth factors. J. Neurochem. 1991, 56: 1107–1113.

    CAS  PubMed  Google Scholar 

  115. Esfandiari A., Gagelin C., Gavaret J.M., Pavelka S., Lennon A.M., Pierre M., Courtin F. Induction of type III-deiodinase activity in astroglial cells by retinoids. Glia 1994, 11: 255–261.

    CAS  PubMed  Google Scholar 

  116. Tu H.M., Legradi G., Bartha, T., Salvatore D., Lechan R.M., Larsen P.R. Regional expression of the type 3 iodothyronine deiodinase messenger ribonucleic acid in the rat central nervous system and its regulation by thyroid hormone. Endocrinology 1999, 140: 784–790.

    CAS  PubMed  Google Scholar 

  117. Escámez M.J., Guadaño-Ferraz A., Cuadrado A., Bernal J. Type 3 iodothyronine deiodinase is selectively expressed in areas related to sexual differentiation in the newborn rat brain. Endocrinology 1999, 140: 5443–5446.

    PubMed  Google Scholar 

  118. Becker K.B., Stephens K.C., Davey J.C., Schneider M.J., Galton V.A. The type 2 and type 3 iodothyronine deiodinases play important roles in coordinating development in Rana catesbeiana tadpoles. Endocrinology 1997, 138: 2989–2997.

    CAS  PubMed  Google Scholar 

  119. Berry D.L., Rose C.S., Remo B.F., Brown D.D. The expression pattern of thyroid hormone response genes in remodeling tadpole tissues defines distinct growth and resorption gene expression programs. Dev. Biol. 1998, 203: 24–35.

    CAS  PubMed  Google Scholar 

  120. Marsh-Armstrong N., Huang H., Remo B.F., Liu T.T., Brown D.D. Asymmetric growth and development of the xenopus laevis retina during metamorphosis is controlled by type III deiodinase. Neuron 1999, 24: 871–878.

    CAS  PubMed  Google Scholar 

  121. Huang H., Marsh-Armstrong N., Brown D.D. Metamorphosis is inhibited in transgenic xenopus laevis tadpoles that overexpress type III deiodinase. Proc. Natl. Acad. Sci. USA 1998, 96: 962–967.

    Google Scholar 

  122. Mortimer R.H., Galligan J.P., Cannell G.R., Addison R.S., Roberts M.S. Maternal to fetal thyroxine transmission in the human term placenta is limited by inner ring deiodination. J. Clin. Endocrinol. Metabol. 1996, 81: 2247–2249.

    CAS  Google Scholar 

  123. Galton V.A., Martínez E., Hernández A., St. Germain E.A., Bates J.M., St.Germain D.L. Pregnant rat uterus expresses high levels of the type 3 iodothyronine deiodinase. J. Clin. Invest. 1999, 103: 979–987.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Baum M.J. Psychosexual development. In: Zigmond M.J., Bloom F.E., Landis S.C., Roberts J.L., (Eds.), Fundamental Neuroscience. Academic Press, San Diego 1999, pp. 1229–1244.

    Google Scholar 

  125. Dellovade T.L., Zhu Y.S., Krey L., Pfaff D.W. Thyroid hormone and estrogen interact to regulate behavior. Proc. Natl. Acad. Sci. USA 1996, 93: 12581–12586.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Lebel J.-M., Dussaul J.H., Puymirat J. Overexpression of the b1 thyroid receptor induces differentiation in neuro-2a cells. Proc. Natl. Acad. Sci. USA 1994, 91: 2644–2648.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Pérez-Juste G., Aranda A. The cyclin-dependent kinase inhibitor p27 (Kip1) is involved in thyroid hormone-mediated neuronal differentiation. J. Biol. Chem. 1999, 19: 5026–5031.

    Google Scholar 

  128. Iñiguez M.A., Rodriguez-Pena A., Ibarrola N., Morreale de Escobar G., Bernal J. Adult rat brain is sensitive to thyroid hormone. Regulation of RC3/neurogranin mRNA. J. Clin. Invest. 1992, 90: 554–558.

    PubMed Central  PubMed  Google Scholar 

  129. Alvarez-Dolado M., Iglesias T., Rodríguez-Peña A., Bernal J., Muñoz A. Expression of neurotrophins and the trk family of neurotrophin receptors in normal and hypothyroid rat brain. Mol. Brain Res. 1994, 27: 249–257.

    CAS  PubMed  Google Scholar 

  130. Mooradian A.D., Li J., Shah G.N. Age-related changes in thyroid hormone responsive protein (THRP) expression in cerebral tissue of rats. Brain Res. 1998, 793: 302–304.

    CAS  PubMed  Google Scholar 

  131. Shah G.N., Li J., Schneiderjohn P., Mooradian A.D. Cloning and characterization of a complementary DNA for a thyroid hormone-responsive protein in mature rat cerebral tissue. Biochem. J. 1997, 327: 617–623.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Bhat N.R., Rao G.S., Pieringer R.A. Investigations on myelination in vitro. Regulation of sulfolipid synthesis by thyroid hormone in cultures of dissociated brain cells from embryonic mice. J. Biol. Chem. 1981, 10: 1167–1171.

    Google Scholar 

  133. Bhat N.R., Shanker G., Pieringer A. Investigations on myelination in vitro. Regulation of 2′–3′-cyclic nucleotide 3′-phosphohydrolase by thyroid hormone in cultures of dissociated brain cells fron embryonic mice. J. Neurochem. 1981, 37: 695–701.

    CAS  PubMed  Google Scholar 

  134. Rodríguez-Peña A., Ibarrola N., Iñiguez M.A., Muñoz A., Bernal J. Neonatal hypothyroidism, affects the timely expression of myelin-associated glycoprotein in the rat brain. J. Clin. Invest. 1993, 91: 812–818.

    PubMed Central  PubMed  Google Scholar 

  135. Ibarrola N., Rodriguez-Peña A. Hypothyroidism coordinately and transiently affects myelin protein gene expression in most rat brain regions during postnatal development. Brain Res. 1997, 752: 285–293.

    CAS  PubMed  Google Scholar 

  136. Strait K.A., Zou L., Oppenheimer J.H. b1 isoform-specific regulation of a triiodothyronine-induced gene during cerebellar development. Mol. Endocrinol. 1992, 6: 1874–1880.

    CAS  PubMed  Google Scholar 

  137. Guadaño-Ferraz A., Escobar del Rey F., Morreale de Escobar G., Innocenti G.M., Berbel P. The development of the anterior commissure in normal and hypothyroid rats. Dev. Brain Res. 1994, 81: 293–308.

    Google Scholar 

  138. Dembri A., Belkhiria M., Michel O., Michel R. Effects of short- and long-term thyroidectomy on mitochondrial and nuclear activity in adult rat brain. Mol. Cell. Endocrinol. 1983, 33: 211–223.

    CAS  PubMed  Google Scholar 

  139. Bangur C.S., Howland J.L., Katyare S.S. Thyroid hormone treatment alters phospholipid composition and membrane fluidity of rat brain mitochondria. Biochem. J. 1995, 305: 29–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Vega-Núñez E., Alvarez A.M., Menendez-Hurtado A., Santos A., Pérez-Castillo A. Neuronal mitochondrial morphology and transmembrane potential are severely altered by hypothyroidism during rat brain development. Endocrinology 1997, 138: 3771–3778.

    PubMed  Google Scholar 

  141. Vega-Núñez E., Menéndez-Hurtado A., Garesse R., Santos A., Perez-Castillo A. Thyroid hormone-regulated brain mitochondrial genes revealed by differential cDNA cloning. J. Clin. Invest. 1995, 96: 893–899.

    PubMed Central  PubMed  Google Scholar 

  142. Alvarez-Dolado M., Gonzalez-Moreno M., Valencia A., Zenke M., Bernal J., Muñoz A. Identification of a mammalian homologue of the fungal Tom70 mitochondrial precursor protein import receptor as a thyroid hormone-regulated gene in specific brain regions. J. Neurochem. 1999, 73: 2240–2249.

    CAS  PubMed  Google Scholar 

  143. Iglesias T., Caubín J., Zaballos A., Bernal J., Muñoz A. Identification of the mitochondrial NADH dehydrogenase subunit 3 (ND3) as a thyroid hormone regulated gene by whole genome PCR analysis. Biochem. Biophys. Res. Comm. 1995, 210: 995–1000.

    CAS  PubMed  Google Scholar 

  144. Patel A.J., Hayashi M., Hunt A. Role of thyroid hormone and nerve growth factor in the development of choline acetyltransferase and other cell-specific marker enzymes in the basal forebrain of the rat. J. Neurochem. 1988, 50: 803–811.

    CAS  PubMed  Google Scholar 

  145. Clos J., Legrand C. An interaction between thyroid hormone and nerve growth factor promotes the development of hippocampus, olfactory bulbs and cerebellum: a comparative biochemical study of normal and hypothyroid rats. Growth Factor 1990, 3: 205–220.

    CAS  Google Scholar 

  146. Figuereido B.C., Almazan G., Ma Y., Tetzlaff W., Miller F.D., Cuello A.C. Gene expression in the developing cerebellum during perinatal hypo- and hyperthyroidism. Mol. Brain Res. 1993, 17: 258–268.

    Google Scholar 

  147. Calzá L., Giardino L., Aloe L. Thyroid hormone regulates NGF content and p75-LNGFR expression in the basal forebrain of adult rats. Exp. Neurol. 1997, 143: 196–206.

    PubMed  Google Scholar 

  148. Lindholm D., Castren E., Tsoulfas P., Kolbeck R., Penha Berzaghi M., Leingartner A., Heisenberg C.P., Tesarollo L., Parada L.F., Thoenen H. Neurotrophin-3 induced by tri-iodothyronine in cerebellar granullar cells promotes purkinje cell differentiation. J. Cell Biol. 1993, 122: 443–450.

    CAS  PubMed  Google Scholar 

  149. Neveu I., Arenas E. Neurotrophins promote the survival and development of neurons in the cerebellum of hypothyroid rats. J. Cell Biol. 1996, 133: 631–646.

    CAS  PubMed  Google Scholar 

  150. Schwartz P.M., Borghesani P.R., Levy R.L., Pomeroy S.L., Segal R.A. Abnormal cerebellar development and foliation in BDNF -/- mice reveals a role of neurotrophins in CNS patterning. Neuron 1997, 19: 269–281.

    CAS  PubMed  Google Scholar 

  151. Koibuchi N., Fukuda H., Chin W.W. Promoter-specific regulation of the brain-derived neurotrophic factor gene by thyroid hormone in the developing rat cerebellum. Endocrinology 1999, 140: 3955–3961.

    CAS  PubMed  Google Scholar 

  152. Vincent J., Legrand C., Rabie A., Legrand J. Effects of thyroid hormone on synaptogenesis in the molecular layer of the developing rat cerebellum. J. Physiol. 1982, 78: 729–38.

    Google Scholar 

  153. Lewis S.A., Lee M.G., Cowan N.J. Five mouse tubulin isotypes and their regulated expression during development. J. Cell Biol. 1985, 101: 852–861.

    CAS  PubMed  Google Scholar 

  154. Wang D., Villasante A., Lewis S.A., Cowan N.J. The mammalian beta-tubulin repertoire: hematopoietic expression of a novel, heterologous beta-tubulin isotype. J. Cell Biol. 1986, 103: 1903–1910.

    CAS  PubMed  Google Scholar 

  155. Aniello F., Couchie D., Gripois D., Nunez J. Regulation of five tubulin isotypes by thyroid hormone during brain development. J. Neurochem. 1991, 57: 1781–1786.

    CAS  PubMed  Google Scholar 

  156. Cleveland D.W. The multitubulin hypothesis revisited: what have we learned? J. Cell Biol. 1987, 104: 381–383.

    CAS  PubMed  Google Scholar 

  157. Nunez J., Couchie D., Aniello F., Bridoux A.M. Regulation by thyroid hormone of microtubule assembly and neuronal differentiation. Neurochem. Res. 1991, 16: 975–982.

    CAS  PubMed  Google Scholar 

  158. Muñoz A., Rodriguez-Peña A., Perez-Castillo A., Ferreiro B., Sutcliffe J.G., Bernal J. Effects of neonatal hypothyroidism on rat brain gene expression. Mol. Endocrinol. 1991, 5: 273–280.

    PubMed  Google Scholar 

  159. Aniello F., Couchie D., Bridoux A.M., Gripois D., Nunez J. Splicing of juvenile and adult tau mRNA variants is regulated by thyroid hormone. Proc. Natl. Acad. Sci. U.S.A. 1991, 88: 4035–4039.

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Silva J.E., Rudas P. Effects of congenital hypothyroidism on microtubule-associated protein-2 expression in the cerebellum of the rat. Endocrinology 1990, 126: 1276–1282.

    CAS  PubMed  Google Scholar 

  161. Milbrandt J. A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science 1987, 238: 797–799.

    CAS  PubMed  Google Scholar 

  162. Mellström B., Pipaon C., Naranjo J.R., Perez-Castillo A., Santos A. Differential effect of thyroid hormone on NGFI-A gene expression in developing rat brain. Endocrinology 1994, 135: 583–588.

    PubMed  Google Scholar 

  163. Ghorbel M.T., Seugnet I., Hadj-Sahraoui N., Topilko P., Levi G., Demeneix B. Thyroid hormone effects on Krox-24 transcription in the post-natal mouse brain are developmentally regulated but are not correlated with mitosis. Oncogene 1999, 18: 917–924.

    CAS  PubMed  Google Scholar 

  164. Denver R.J., Ouellet L., Furling D., Kobayashi A., Fujii-Kuriyama Y., Puymirat J. Basic transcription element-binding protein (BTEB) is a thyroid hormone-regulated gene in the developing central nervous system. Evidence for a role in neurite outgrowth. J. Biol. Chem. 1999, 274: 23128–23134.

    CAS  PubMed  Google Scholar 

  165. Giguere V., Tini M., Flock G., Ong E., Evans R.M., Otulakowski G. Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev. 1994, 8: 538–553.

    CAS  PubMed  Google Scholar 

  166. Sashihara S., Felts P.A., Waxman S.G., Matsui, T. Orphan nuclear receptor ROR alpha gene: isoformspecific spatiotemporal expression during postnatal development of brain. Mol. Brain Res. 1996, 42: 109–117.

    CAS  PubMed  Google Scholar 

  167. Hamilton B.A., Frankel W.N., Kerrebrock A.W., Hawkins T.L., FitzHugh W., Kusumi K., Russell L.B., Mueller K.L., van Berkel V., Birren B.W., Kruglyak L., Lander E.S. Disruption of the nuclear hormone receptor RORalpha in staggerer mice [published erratum appears in Nature 1996 May 23; 381 (6580): 346]. Nature 1996, 379: 736–739.

    CAS  PubMed  Google Scholar 

  168. Koibuchi N., Chin W.W. RORa gene expression in the perinatal rat cerebellum: ontogeny and thyroid hormone regulation. Endocrinology 1998, 139: 2335–2341.

    CAS  PubMed  Google Scholar 

  169. Koibuchi N., Liu Y., Fukuda H., Takeshita A., Yen P.M., Chin W.W. ROR alpha augments thyroid hormone receptor-mediated transcriptional activation. Endocrinology 1999, 140: 1356–1364.

    CAS  PubMed  Google Scholar 

  170. Matsui T. Transcriptional regulation of a Purkinje cell-specific gene through a functional interaction between ROR alpha and RAR. Genes Cells 1997, 2: 263–272.

    CAS  PubMed  Google Scholar 

  171. Alvarez-Dolado M., Gonzalez-Sancho J.M., Bernal J., Muñoz A. Developmental expression of tenascin-C is altered by hypothyroidism in the rat brain. Neuroscience 1998, 84: 309–322.

    CAS  PubMed  Google Scholar 

  172. Latasa M.J., Belandia A., Pascual A. Thyroid hormones regulates β-amyloid gene splicing and protein secretion in neuroblastoma cells. Endocrinology 1998, 139: 2692–2697.

    CAS  PubMed  Google Scholar 

  173. Gerrelli D., Huntriss J.D., Latchman, D.S. Antagonistic effects of retinoic acid and thyroid hormone on the expression of the tissue splicing protein SmN in a clonal cell line derived from rat heart. J. Mol. Cell. Cardiol. 1994, 26: 713–719.

    CAS  PubMed  Google Scholar 

  174. Cuadrado A., Bernal J., Muñoz A. Identification of the mammalian homolog of the splicing regulator Suppressor-of-white-apricot as a thyroid hormone regulated gene. Mol. Brain. Res. 1999, 71: 332–340.

    CAS  PubMed  Google Scholar 

  175. Iglesias T., Caubin J., Stunnenberg H.G., Zaballos A., Bernal J., Muñoz A. Thyroid hormone-dependent transcriptional repression of neural cell adhesion molecule during brain maturation. EMBO J. 1996, 15: 4307–4316.

    CAS  PubMed Central  PubMed  Google Scholar 

  176. Alvarez-Dolado M., Cuadrado A., Navarro-Yubero C., Sonderegger P., Furley A.J., Bernal J., Muñoz A. Regulation of the L1 cell adhesion molecule by thyroid hormone in the developing brain. Mol. Cell. Neurobiol. 2000, 499–514.

    Google Scholar 

  177. Farwell A.P., Dubord-Tomasetti S.A. Thyroid hormone regulates the expression of laminin in the developing rat cerebellum. Endocrinology 1999, 140: 4221–4227.

    CAS  PubMed  Google Scholar 

  178. Gilmore E.C., Herrup K. Cortical development: receiving reelin. Curr. Biol. 2000, 10: R162–6.

    CAS  PubMed  Google Scholar 

  179. Gerendasy D.D., Sutcliffe J.G. RC3/neurogranin, a postsynaptic calpacitin for setting the response threshold to calcium influxes. Mol. Neurobiol. 1997, 15: 131–163.

    CAS  PubMed  Google Scholar 

  180. Iñiguez M.A., Rodriguez-Peña A., Ibarrola N., Aguilera M., Muñoz A., Bernal J. Thyroid hormone regulation of RC3, a brain-specific gene encoding a protein kinase-C substrate. Endocrinology 1993, 133: 467–473.

    PubMed  Google Scholar 

  181. Piosik P.A., van Groenigen M., Baas F. Effect of thyroid hormone deficiency on RC3/neurogranin mRNA expression in the prenatal and adult caprine brain. Mol. Brain Res. 1996, 42: 227–235.

    CAS  PubMed  Google Scholar 

  182. Iñiguez M.A., De Lecea L., Guadaño-Ferraz A., Morte B., Gerendasy D., Sutcliffe J.G., Bernal J. Cell-specific effects of thyroid hormone on RC3/neurogranin expression in rat brain. Endocrinology 1996, 137: 1032–1041.

    PubMed  Google Scholar 

  183. Guadaño-Ferraz A., Escámez M.J., Morte B., Vargiu, P., Bernal J. Transcriptional induction of RC3/neurogranin by thyroid hormone: differential neuronal sensitivity is not correlated with thyroid hormone receptor distribution in the brain. Mol. Brain Res. 1997, 49: 37–44.

    PubMed  Google Scholar 

  184. Morte B., Iñiguez M.A., Lorenzo P.I., Bernal J. Thyroid hormone-regulated expression of RC3/neurogranin in the immortalized hypothalamic cell line GT1-7. J. Neurochem. 1997, 69: 902–909.

    CAS  PubMed  Google Scholar 

  185. Martinez de Arrieta C., Morte B., Coloma A., Bernal J. The human RC3 gene homolog, NRGN contains a thyroid hormone-responsive element located in the first intron. Endocrinology 1999, 140: 335–343.

    CAS  PubMed  Google Scholar 

  186. Morte B., Martínez de Arrieta C., Manzano J., Coloma A., Bernal J. Identification of a cis-acting element that interferes with thyroid hormone induction of the Neurogranin (NRGN) gene. FEBS Lett. 1999, 464: 179–183.

    CAS  PubMed  Google Scholar 

  187. Pak J.H., Huang F.L., Li J., Balschun D., Reymann K.G., Chiang C., Westphal H., Huang K.P. Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: a study with knockout mice. Proc. Natl. Acad. Sci. USA 2000, 97: 11232–11237.

    CAS  PubMed Central  PubMed  Google Scholar 

  188. Soderling T.R. The Ca-calmodulin-dependent protein kinase cascade. Trends Biochem. Sci. 1999, 24: 232–236.

    CAS  PubMed  Google Scholar 

  189. Anderson K.A., Means R.L., Huang Q.H., Kemp B.E., Goldstein E.G., Selbert M.A., Edelman A.M., Fremeau R.T., Means A.R. Components of a calmodulin-dependent protein kinase cascade. Molecular cloning, functional characterization and cellular localization of Ca2+/calmodulin-dependent protein kinase kinase beta. J. Biol. Chem. 1998, 273: 31880–31889.

    CAS  PubMed  Google Scholar 

  190. Krebs J., Means R.L., Honegger P. Induction of calmodulin kinase IV by the thyroid hormone during the development of rat brain. J. Biol. Chem. 1996, 271: 11055–11058.

    CAS  PubMed  Google Scholar 

  191. Krebs J., Honegger P. Calmodulin kinase IV: expression and function during rat brain development. Biochim. Biophys. Acta 1996, 1313: 217–22.

    PubMed  Google Scholar 

  192. Kuno-Murata M., Koibuchi N., Fukuda H., Murata M., Chin W.W. Augmentation of thyroid hormone receptor-mediated transcription by Ca2+/calmodulin-dependent protein kinase type IV. Endocrinology 2000, 141: 2275–2278.

    CAS  PubMed  Google Scholar 

  193. Falk J.D., Vargiu P., Foye P.E., Usui H., Pérez J., Danielson P.E., Lerner, D.L., Bernal J., Sutcliffe J.G. Rhes: a striatal-specific Ras homolog related to Dexras1. J. Neurosci. Res. 1999, 57: 782–788.

    CAS  PubMed  Google Scholar 

  194. Urade Y., Hayaishi O. Prostaglandin D synthase: structure and function. Vit. Horm. 2000, 58: 89–120.

    CAS  Google Scholar 

  195. García-Fernández L.F., Iñiguez M.A., Rodríguez-Peña A., Muñoz A., Bernal J. Brain-specific prostaglandin D2 synthetase mRNA is dependent on thyroid hormone during rat brain development. Biochem. Biophys. Res. Comm. 1993, 196: 396–401.

    PubMed  Google Scholar 

  196. García-Fernández L.F., Urade Y., Hayaishi O., Bernal J., Muñoz A. Identification of a thyroid hormone response element in the promoter region of the rat lipocalin-type prostaglandin D synthase (beta-trace) gene. Mol. Brain Res. 1998, 55: 321–330.

    PubMed  Google Scholar 

  197. White D.M., Takeda T., DeGroot L.J., Stefansson K., Arnason B.G. Beta-trace gene expression is regulated by a core promoter and a distal thyroid hormone response element. J. Biol. Chem. 1997, 272: 14387–14393.

    CAS  PubMed  Google Scholar 

  198. Zou L., Hagen S.C., Strait K.A., Oppenheimer J.H. Identification of thyroid hormone response elements in rodent Pcp-2, a developmentally regulated gene of cerebellar Purkinje cells. J. Biol. Chem. 1994, 269: 13346–13352.

    CAS  PubMed  Google Scholar 

  199. Anderson G.W., Hagen S.G., Larson R.J., Strait K.A., Schwartz H.L., Mariash C.N., Oppenheimer J.H. Purkinje cell protein-2 cis-elements mediate repression of T3-dependent transcriptional activation. Mol. Cell. Endocrinol. 1997, 131: 79–87.

    CAS  PubMed  Google Scholar 

  200. Anderson G.W., Larson R.J., Oas D.R., Sandhofer C.R., Schwartz H.L., Mariash C.N., Oppenheimer J.H. Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) modulates expression of the Purkinje cell protein-2 gene. A potential role for COUP-TF in repressing premature thyroid hormone action in the developing brain. J. Biol. Chem. 1998, 273: 16391–16399.

    CAS  PubMed  Google Scholar 

  201. Thompson C.C. Thyroid hormone-responsive genes in developing cerebellum include a novel synaptotagmin and a hairless homolog. J. Neurosci. 1996, 16: 7832–7840.

    CAS  PubMed  Google Scholar 

  202. Faivre-Sarrailh C., Ferraz C., Liautard J.P., Rabie A. Effect of thyroid deficiency on actin mRNA content in the developing rat cerebellum. Int. J. Dev. Neurosci. 1990, 8: 99–106.

    CAS  PubMed  Google Scholar 

  203. Koibuchi N., Matsuzaki S., Ichimura K., Ohtake H., Yamaoka S. Ontogenic changes in the expression of cytochrome c oxidase subunit I gene in the cerebellar cortex of the perinatal hypothyroid rat. Endocrinology 1996, 137: 5096–5108.

    CAS  PubMed  Google Scholar 

  204. Forrest D., Vennström B. Functions of thyroid hormone receptors in mice. Thyroid 2000, 10: 41–52.

    CAS  PubMed  Google Scholar 

  205. Forrest D., Hanebuth E., Smeyne R.J., Everds N., Stewart C.L., Wehner J.M., Curran T. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function. EMBO J. 1996, 15: 3006–30015.

    CAS  PubMed Central  PubMed  Google Scholar 

  206. Forrest D., Golarai G., Connor J., Curran T. Genetic analysis of thyroid hormone receptors in development and disease. Rec. Prog. Horm. Res. 1996, 51: 1–22.

    CAS  PubMed  Google Scholar 

  207. Sandhofer C., Schwartz H.L., Mariash C.N., Forrest D., Oppenheimer J.H. Beta receptor isoforms are not essential for thyroid hormone-dependent acceleration of PCP-2 and myelin basic protein gene expression in the developing brains of neonatal mice. Mol. Cell. Endocrinol. 1998, 137: 109–115.

    CAS  PubMed  Google Scholar 

  208. Fraichard A., Chassande O., Plateroti M., Roux J.P., Trouillas J., Dehay C., Legrand C., Gauthier K., Kedinger M., Malaval L., Rousset B., Samarut J. The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production. EMBO J. 1997, 16: 4412–4420.

    CAS  PubMed Central  PubMed  Google Scholar 

  209. Gothe S., Wang Z., Ng L., Kindblom J.M., Barros A.C., Ohlsson C., Vennstrom B., Forrest D. Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitarythyroid axis, growth, and bone maturation. Genes Dev. 1999, 13: 1329–1341.

    CAS  PubMed Central  PubMed  Google Scholar 

  210. Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr. Rev. 1997, 18: 401–433.

    Google Scholar 

  211. Maberly G.F. Iodine deficiency disorders: contemporary scientific issues. J. Nutr. 1994, 124: 1473S–1478S.

    CAS  PubMed  Google Scholar 

  212. Merke F. The history and iconography of endemic goiter and cretinism MTP Press, Lancaster, 1984.

    Google Scholar 

  213. McCarrison R. Endemic cretinism. In: The thyroid gland in health and disease. Bailliére, Tindall and Cox, London, 1917, p. 124.

    Google Scholar 

  214. DeLong G.R., Stanbury J.B., Fierro-Benitez R. Neurological signs in congenital iodine-deficiency disorder (endemic cretinism). Dev. Med. Child Neurol. 1985, 27: 317–324.

    CAS  PubMed  Google Scholar 

  215. Thilly C.H., Bourdoux P.P., Due, D.T., DeLong G.R., Vanderpas J.B., Ermans A.M. Myxedematous cretinism: an indicator of the most severe goiter endemias. In: Medeiros-Neto E., Gaitan E. (Eds.), Frontiers in thyroidology. Plenum Press, New York, 1986, p. 1081.

    Google Scholar 

  216. Contempré B., Dumont J.E., Denef J.F., Many M.C. Effects of selenium deficiency on thyroid necrosis, fibrosis and proliferation: a possible role in myxoedematous cretinism. Eur. J. Endocrinol. 1995, 133: 99–109.

    PubMed  Google Scholar 

  217. Contempre B., Le Moine O., Dumont J.E., Denef J.F., Many M.C. Selenium deficiency and thyroid fibrosis. A key role for macrophages and transforming growth factor beta (TGF-beta). Mol. Cell Endocrinol. 1996, 124: 7–15.

    CAS  PubMed  Google Scholar 

  218. Pharoah P.O., Buttfield I.H., Hetzel B.S. Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet 1971, 1: 308–310.

    CAS  PubMed  Google Scholar 

  219. Pharoah P.O., Connolly K.J. Effects of maternal iodine supplementation during pregnancy. Arch. Dis. Child. 1991, 66: 145–147.

    CAS  PubMed Central  PubMed  Google Scholar 

  220. Delange F. Neonatal screening for congenital hypothyroidism: results and perspectives. Hormone Res. 1997, 48: 51–61.

    CAS  PubMed  Google Scholar 

  221. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis, and management. Thyroid 1999, 9: 735–740.

    CAS  PubMed  Google Scholar 

  222. Dubois J.-M., Glorieux J., Richer F., Deal C.L., Dussault J.H., Van Vliet G. Outcome of severe congenital hypothyrodism: closing the developmental gap with early high dose levothyroxine treatment. J. Clin. Endocrinol. Metabol. 1996, 81: 222–227.

    Google Scholar 

  223. de Zegher F., Pernasetti F., Vanhole C., Devlieger H., Van den Berghe G., Martial J.A. The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency. J. Clin. Endocrinol. Metab. 1995, 80: 3127–3130.

    PubMed  Google Scholar 

  224. Blizzard R.M., Chandler R.W., Landing Pettit M.D., West C.D. Maternal autoimmunization to thyroid as probable cause of athyreotic cretinism. N. Engl. J. Med. 1960, 263: 327–336.

    CAS  PubMed  Google Scholar 

  225. Yasuda T., Ohnishi H., Wataki K., Minagawa M., Minamitami K., Niimi H. Outcome of a baby born from a mother with acquired juvenile hypothyroidism having undetectable thyroid hormone concentrations. J. Clin. Endocrinol. Metabol. 1999, 84: 2630–2632.

    CAS  Google Scholar 

  226. Haddow J.E., Palomäki G.E., Allan W.C., Williams J.R., Knight G.J., Gagnon J., O’Heir C.E., Mitchell M.L., Hermos R.J., Waisbren S.E., Faix J.D., Klein R.Z. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N. Engl. J. Med. 1999, 341: 549–555.

    CAS  PubMed  Google Scholar 

  227. Utiger R.D. Maternal hypothyroidism ad fetal development. N. Engl. J. Med. 1999, 341: 601–602.

    CAS  PubMed  Google Scholar 

  228. Pop V.J., Kuijpens J.L., van Baar A.L., Verkerk G., van Son M.M., de Vijlder J.J., Vulsma T., Wiersinga W.M., Drexhage H.A., Vader H.L. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin. Endocrinol. (Oxf.) 1999, 50: 149–155.

    CAS  Google Scholar 

  229. Morreale de Escobar G., Escobar del Rey F. Letter to the editor. N. Engl. J. Med. 1999, 26: 2016–2017.

    Google Scholar 

  230. Reuss M.L., Levinton A., Paneth N., Susser M. Thyroxine values from newborn screening of 919 infants born before 29 week’s gestation. Am. J. Publ. Health 1997, 87: 1693–1697.

    CAS  Google Scholar 

  231. Fisher D.A. Thyroid function in premature infants. The hypothyroxinemia of prematurity. Clin. Perinatol. 1998, 25: 999–1014.

    CAS  PubMed  Google Scholar 

  232. van den Hove M.F., Beckers C., Devlieger H., de Zegher F., De Nayer P. Hormone synthesis and storage in the thyroid of human preterm and term newborns: effect of thyroxine treatments. Biochimie 1999, 81: 563–570.

    PubMed  Google Scholar 

  233. Ares S., Escobar-Morreale H., Quero J., Duran S., Presas M.J., Herruzo R., Morreale de Escobar G. Neonatal hypothyroxinemia: effects of iodine intake and premature birth. J. Clin. Endocrinol. Metabol. 1997, 82: 1704–1712.

    Google Scholar 

  234. Morreale de Escobar G., Ares S. The hypothyroxinemia of prematurity. J. Clin. Endocrinol. Metabol. 1998, 83: 713–715.

    CAS  Google Scholar 

  235. Thorpe-Beeston J.G., Nicolaides K.H., Felton C.V., Butler J., McGregor A.M. Maturation of the secretion of thyroid hormone and thyroid stimulating hormone in the fetus. N. Engl. J. Med. 1991, 324: 532–536.

    CAS  PubMed  Google Scholar 

  236. Den Ouden A.L., Kok J.H., Verkerk P.H., Brand R., Verloove-Vanhorick S.P. The relation between neonatal thyroxine levels ad neurodevelopmental outcome at age 5 and 9 years in a national cohort of very preterm and/or very low birth weight infants. Pediatr. Res. 1996, 39: 142–145.

    Google Scholar 

  237. Reuss M.L., Paneth N., Pinto-Martin J.A., Lorenz J.M., Susser M. The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age. N. Engl. J. Med. 1996, 334: 821–827.

    CAS  PubMed  Google Scholar 

  238. Levinton A., Paneth N., Reuss M.L., Susser M., Allred E.N., Dammann O., Kubak K., Van Marter L.J., Pagano M. Hypothyroxinemia of prematurity and the risk of cerebral white matter damage. J. Pediatr. 1999, 134: 706–711.

    Google Scholar 

  239. Fisher D.A. Hypothyroxinemia in premature infants: is thyroxine treatment necessary? Thyroid 1999, 9: 715–720.

    CAS  PubMed  Google Scholar 

  240. Van Wassenaer A.G., Kok J.H., De Vijlder J.J., Briet J.M., Smit B.J., Tamminga P., van Baar, A., Dekker F.W., Vulsma T. Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks’ gestation. N. Engl. J. Med. 1997, 336: 21–26.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J. Bernal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bernal, J. Action of thyroid hormone in brain. J Endocrinol Invest 25, 268–288 (2002). https://doi.org/10.1007/BF03344003

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03344003

Key-words

Navigation