Article thumbnail

Thyroid Hormone and the Neuroglia: Both Source and Target

By Petra Mohácsik, Anikó Zeöld, Antonio C. Bianco and Balázs Gereben


Thyroid hormone plays a crucial role in the development and function of the nervous system. In order to bind to its nuclear receptor and regulate gene transcription thyroxine needs to be activated in the brain. This activation occurs via conversion of thyroxine to T3, which is catalyzed by the type 2 iodothyronine deiodinase (D2) in glial cells, in astrocytes, and tanycytes in the mediobasal hypothalamus. We discuss how thyroid hormone affects glial cell function followed by an overview on the fine-tuned regulation of T3 generation by D2 in different glial subtypes. Recent evidence on the direct paracrine impact of glial D2 on neuronal gene expression underlines the importance of glial-neuronal interaction in thyroid hormone regulation as a major regulatory pathway in the brain in health and disease

Topics: Review Article
Publisher: SAGE-Hindawi Access to Research
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (2002). A .C .B i a n c o ,D .S a l v a t o r
  2. (2004). A .M .D u m i t r e s c u ,X .H .L i a o ,T .B .B e s t ,K .B r o c k m a n n
  3. (2005). a n s e n ,E .C .H .F r i e s e m a ,C .M i l i c i ,a n dT .J .V i s s e r , “Thyroid hormone transporters in health and disease,”
  4. (1994). A thyroid hormone-regulated gene in Xenopus laevis encodes a type III iodothyronine
  5. (2008). A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function,”JournalofNeuroscience,vol.28,no.1,pp.264–278,
  6. (2004). Aberrant maturation of Astrocytes in Thyroid hormone receptor α1 knockout mice reveals an interplay between Thyroid hormone receptor isoforms,”
  7. (1997). Accumulation of the cyclin-dependent kinase inhibitor p27/Kip1 and the timing of oligodendrocyte differentiation,”
  8. (1979). Adult rat brain astrocytes support survival of both NGF-dependent and NGF-insensitive neurones,”
  9. (2005). AllanHerndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene,”
  10. An analysis of the sources and quantity of 3,5,3’-triiodothyronine specifically bound to nuclear receptors in rat cerebral cortex and cerebellum,”
  11. (2004). Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation,”
  12. (2011). Bacterial lipopolysaccharide induces type 2 deiodinase in cultured rat astrocytes,”
  13. (1994). C a r l s o n ,K .A .S t r a i t ,H .L .S c h w a r t z ,a n dJ .H . Oppenheimer, “Immunofluorescent localization of thyroid hormone receptor isoforms in glial cells of rat brain,”
  14. (1996). C a r l s o n ,K .A .S t r a i t ,H .L .S c h w a r t z ,a n dJ .H . Oppenheimer, “Thyroid hormone receptor isoform content
  15. (2007). C.Fekete,B.C.G.Freitas,A.Ze¨ oldetal.,“Expressionpatterns of WSB-1 and USP-33 underlie cell-specific posttranslational control of type 2 deiodinase in the rat brain,”
  16. (2002). Cell cycle control by the thyroid hormone in neuroblastoma cells,”
  17. (2008). Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling,”
  18. (1999). Cerebellar astrocytes treated by thyroid hormone modulate neuronal proliferation,”
  19. (1981). Cerebral cortex responds rapidly to thyroid hormones,”
  20. (1968). Changes in thyroid secretion produced by inhibition of iodotyrosine deiodinase,”
  21. (2000). Characterization of the 5’-flanking and 5’-untranslated regions of the cyclic adenosine 3’,5’-monophosphate-responsive human type 2 iodothyronine deiodinase gene,”
  22. (2006). Characterization of the nuclear factor-κB responsiveness of the human dio2 gene,”
  23. (2005). Christoffo l e t e ,C .H .E m e r s o n ,A
  24. Christofollete et al., “Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation,”
  25. (2006). Chronic local inflammation in mice results in decreased TRH and type 3 deiodinase mRNA expression in the hypothalamic paraventricular nucleus independently of diminished food intake,”
  26. Cloning and expression of a cDNA for a mammalian type III iodothyronine deiodinase,”
  27. (1999). Cloning and expression of the chicken type 2 iodothyronine 5’—deiodinase,”
  28. (1995). Cloning of a cDNA for the type II iodothyronine deiodinase,”
  29. (1996). Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues,”
  30. (2010). Contribution of TNF-α and nuclear factor-κB signaling to type 2 iodothyronine deiodinase activation in the mediobasal hypothalamus after lipopolysaccharide administration,”
  31. (1994). Correlative regulation of nerve growth factor level and choline acetyltransferase activity by thyroxine in particular regions of infant rat brain,”
  32. (2001). Critical role for thyroid hormone receptor β2 in the regulation of paraventricular thyrotropin-releasing hormone neurons,”
  33. (1999). Dangerous dogmas in medicine: the nonthyroidal illness syndrome,”
  34. (1980). Decreased extrathyroidal triidodothyronine production in nonthyroidal illness: benefit or harm?”
  35. (2006). Deiodinases: implications of the local control of thyroid hormone action,”
  36. Dentice et al., “Metabolic instability of type 2 deiodinase is transferable to stable proteins independently of subcellular localization,”
  37. (2011). Developmental and celltype-specificexpressionofthyroidhormonetransporters in the mouse brain and in primary brain cells,”
  38. (1988). Dibutyryl cAMP induction of type II 5’deiodinase activity in rat brain astrocytes in culture,”
  39. (2011). Dumitrescu et al., “Distinct roles of deiodinases on the phenotype of Mct8 defect: a comparison of eight different mouse genotypes,”
  40. (2010). E.H.F¨ uzesi,E.Szab´ o,M.Doleschalletal.,“Developmental co-expression of type 2 deiodinase (D2) and
  41. (2009). E.K.Wirth,S.Roth,C.Blechschmidtetal.,“Neuronal3,3,5-triiodothyronine (T3) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T3 transporter mutated in Allan-Herndon-Dudley syndrome,”
  42. (2002). Early expression of thyroid hormone deiodinases and receptors in human fetal cerebral cortex,”
  43. (1991). Effect of thyroid deficiency on glial fibrillary acidic protein (GFAP) and GFAP-mRNA in the cerebellum and hippocampal formation of the developing rat,” Glia,v o l .4 ,n o .3 ,p p .
  44. (2008). Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10,” Molecular Endocrinology,
  45. Effects of hyperand hypothyroidism on thyroid hormone concentrations in regions of the rat brain,”
  46. (2003). Endoplasmic reticulum-associated degradation of the human Type 2 iodothyronine deiodinase (D2) is mediated via an association between mammalian UBC7 and the carboxyl region of D2,”
  47. (1997). Euthyroid sick syndrome: an overview,”
  48. (1988). Evidence for the presence of nuclear 3,5,3’-triiodothyronine receptors in secondary cultures of pure rat oligodendrocytes,”
  49. (2008). Expression of the thyroid hormone transporters monocarboxylate transporter-8 (SLC16A2) and organic ion transporter-14 (SLCO1C1) at the blood-brain barrier,”
  50. (1997). Expression of the type II iodothyronine deiodinase in cultured rat astrocytesisselenium-dependent,”JournalofBiologicalChemistry,
  51. (2003). Expression of type 2 deiodinase in the developing chicken brain,”
  52. (1999). Expression of type 2 iodothyronine deiodinase in hypothyroidratbrainindicatesanimportantroleofthyroidhormone in the development of specific primary sensory systems,”
  53. (1999). Expression profiles of the three iodothyronine deiodinases,
  54. (1998). Fastinginduced increase in type II iodothyronine deiodinase activity a n dm e s s e n g e rr i b o n u c l e i ca c i dl e v e l si sn o tr e v e r s e db y thyroxine in the rat hypothalamus,”
  55. (2004). Feedback regulation of thyrotropin-releasing hormone (TRH): mechanisms for the non-thyroidal illness syndrome,”
  56. G a l t o n ,E .T .W o o d
  57. (2006). G r e e n b e r g ,M .R e i v i c h ,J .T .G o r d o n ,M .B .S c h o e n h o
  58. (2000). Gene regulation by thyroid hormone,”
  59. (2004). Getting a GR(i)P on oligodendrocyte development,”
  60. (1999). Glial fibrillary acidic protein (GFAP): modulation by growth factors and its implication in astrocyte differentiation,”
  61. (1994). Glial fibrillary acidic protein: regulation by hormones, cytokines, and growth factors,”
  62. (1997). Glial lineages and myelination in the central nervous system,”
  63. (2000). Gliogenesis in the central nervous system,” GLIA,v o l .3 0 ,n o .2 ,p p .
  64. (2003). Guada˜ n o - F e r r a z ,a n dB .M o r t e ,“ P e r s p e c t i v e si n the Study of Thyroid hormone action on brain development and function,”
  65. (2003). Hormone-dependent repression of the E2F-1 gene by thyroid hormone receptors,”
  66. (2007). Hypothalamic thyroid hormone catabolism acts as a gatekeeper for the seasonal control of body weight and reproduction,”
  67. (2007). Hypoxia stabilizes type 2 deiodinase activity in rat astrocytes,”
  68. (2003). hyroid Physiology and Diagnostic Evaluation of Patients with Thyroid Disorders,”
  69. (1986). Identification and characterization of L-triiodothyronine receptors in cells of glial and neuronal origin,”
  70. (2010). IGF-I stimulates neurogenesis in the hypothalamus of adult rats,”
  71. (1990). Induction of 5’-deiodinase activity in rat astroglial cells by acidic fibroblast growth factor,”
  72. (2008). Induction of type 2 iodothyronine deiodinase in the mediobasal hypothalamus by bacterial lipopolysaccharide: role of corticosterone,”
  73. (1989). Induction of type II 5’-deio-dinase activity in cultured rat astroglial cells by 12-O-tetra-decanoylphorbol-13-acetate: dependence on glucocorticoids,”
  74. (1988). Induction of type II 5’-deiodinase activity by cyclic adenosine 3’,5’-monophosphate in cultured rat astroglial cells,”
  75. (2007). Influence of thyroid hormones on maturation of rat cerebellar astrocytes,”
  76. (1975). Influence of thyroid hormones on myelin proteins in the developing rat brain,”
  77. (2005). Insights into the role of deiodinases from studies of genetically modified animals,”
  78. (2004). Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas,”
  79. (2000). Isolation of human type 2 deiodinase gene promoter and characterization of a functional cyclic adenosine monophosphate response element,”
  80. (2009). Life without thyroxine to 3,5,3’-triiodothyronine conversion: studies in mice devoid of the 5’-deiodinases,”
  81. (2003). Light-induced hormone conversion of T4 to T3 regulates photoperiodic response of gonads in birds,”
  82. (2004). Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: implications for the nonthyroidal illness syndrome,”
  83. (2011). Local control of thyroid hormone action: role of type 2 deiodinase: deiodinases: the balance of thyroid hormone,”
  84. Long-day suppressed expressionoftype2deiodinasegeneinthemediobasal hypothalamusoftheSaanengoat,ashort-daybreeder:implication forseasonalwindowofthyroidhormoneactiononreproductive neuroendocrine axis,”
  85. (1999). Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy,”
  86. (1997). Mart´ ınez-Gal´ a n ,P .P e d r a z a ,M .S a n t a c a n a
  87. (1999). Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child,”
  88. (2009). Miniereview: defining the roles of the lodothyronine deiodinases:currentconceptsandchallenges,”Endocrinology,
  89. (2010). Molecular aspects of thyroid hormone actions,”
  90. (1997). Molecular basis of thyroid hormone-dependent brain development,”
  91. (1996). Molecular biological and biochemical characterization of the human type 2 selenodeiodinase,”
  92. (2008). Multigenic control of thyroid hormone functions in the nervous system,”
  93. (2007). Negative feedback regulation of hypophysiotropic thyrotropin-releasing hormone (TRH) synthesizing neurons: role of neuronal afferents and type 2 deiodinase,”
  94. (1993). Neonatal hypothyroidism affects the timely expression of myelin- associated glycoprotein in the rat brain,”
  95. Neuritogenesis induced by thyroid hormone-treated astrocytes is mediated by epidermal growth factor/mitogen-activated protein kinasephosphatidylinositol 3-kinase pathways and involves modulation of extracellular matrix proteins,”
  96. (2008). Neurodevelopmental and neurophysiological actions of thyroid hormone,”
  97. (1995). Neuroendocrine regulation of adrenal gland and hypothalamus 5’deiodinase activity.II.Effectsofsplanchnicotomyandhypophysectomy,”
  98. (1995). Neuroglia,O x f o r d
  99. New insights into the role of thyroid hormone in the CNS: the microglial track,”
  100. (2008). Non-genomic actions of thyroid hormone in brain development,”
  101. (1994). noz, “Expression of neurotrophins and the trk family of neurotrophin receptors in normal and hypothyroid rat brain,” Molecular Brain Research,v o l .2 7 ,n o .2 ,p p .
  102. (1990). Nuclear tri-iodothyronine(T3)bindinginneonatalratbrainsuggests a direct glial requirement for T3 during development,”
  103. (1997). Obreg´ o n ,D .L .S .G e r m a i n ,a n dJ . Bernal, “The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain,”
  104. (1999). Oligodendrocyte development and thyroid hormone,” J o u r n a lo fN e u r o b i o l o gy ,v o l .4 0 ,n o .4 ,p p .
  105. (1984). Ontogenesis of the nuclear 3,5,3’-triiodothyronine receptor in the human fetal brain,”
  106. (2010). Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells,”
  107. (1996). Phenolic and tyrosyl ring iodothyronine deiodination and thyroid hormone concentrations in the human central nervous system,”
  108. (2004). Photoperiodic regulation of type 2 deiodinase gene in djungarian hamster: possible homologies between avian and mammalian photoperiodic regulation of reproduction,”
  109. (2005). Pretranslational regulation of type 2
  110. Prevalence of abnormal thyroid function test results in patients with acute medical illnesses,”
  111. (1998). Rat brain type II 5’-iodothyronine deiodinase activity is extremely sensitive to stress,”
  112. (2008). Redout et al., “Hypoxia-inducible factor induces local thyroid hormone inactivationduringhypoxic-ischemicdiseaseinrats,”Journal of Clinical Investigation,
  113. (1997). Regional distribution of type 2 thyroxine deiodinase messenger ribonucleic acid in rat hypothalamus and pituitary and its regulation by thyroid hormone,”
  114. (2001). Regional physiological adaptation of the central nervous system deiodinases to iodine deficiency,”
  115. (2001). Regulation of microglial development: a novel role for thyroid hormone,”
  116. (2010). Regulation of oligodendrocyte differentiation and myelination,”
  117. Report of the committee of the clinical society of london nominated December 14, 1883, to investigate the subject of myxoedema,”
  118. Rodr´ ıguez-Pe˜ na, “Hypothyroidism coordinately and transiently affects myelin protein gene expression in most rat brain regions during postnatal development,”BrainResearch,vol.752,no.1-2,pp.285–293,1997.
  119. Role of thyroid hormone deiodination in the hypothalamus,”
  120. (1994). Role of thyroid hormones in the maturation of interhemispheric connections of rats,”
  121. (1997). S t r a i t ,D .J .C a r l s o n ,H .L .S c h w a r t z ,a n dJ .H . Oppenheimer,“Transientstimulationofmyelinbasicprotein gene expression in differentiating cultured oligodendrocytes: a model for 3,5,3’- triiodothyronine-induced brain development,”
  122. (1996). S.P aul,R.P oddar ,andP .K.Sarkar ,“Roleofth yroidhormone in the morphological differentiation and maturation of astrocytes: temporal correlation with synthesis and organization of actin,”
  123. (2009). Sanchez-Mendoza et al., “Importance of monocarboxylate transporter 8 for the blood-brain barrier-dependent availability of 3,5,3’ -triiodoL-thyronine,”
  124. (2000). Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation,”
  125. (1996). Serum free 3,5,3’-triiodothyronine (T3) in non-thyroidal somatic illness, as measured by ultrafiltration and immunoextraction,”
  126. (2004). Simultaneous changes in central and peripheral components of the hypothalamuspituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice,”
  127. (2007). Sonic hedgehoginduced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes,”
  128. (2000). Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradationandrequiresinteractionwiththeenzyme’sactive center,”
  129. (1999). SWiP-1: novel SOCS box containing WD-protein regulated by signalling centres and by Shh during development,”
  130. (1999). T u ,G .L e g r a d i ,T .B a r t h a ,D .S a l v a t o r e ,R
  131. (1995). T3 affects cerebellar astrocyte proliferation,
  132. (2006). Targeted disruption of the type 1 selenodeiodinase gene (Dio1) results in marked changes in thyroid hormone economy in mice,”
  133. (2001). Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4,” Molecular Endocrinology ,
  134. (2008). The balance between oligodendrocyte and astrocyte production in major white matter tracts is linearly related to serum total thyroxine,”
  135. (1999). The cyclin-dependent kinase inhibitor p27(Kip1) is involved in thyroid hormonemediated neuronal differentiation,”
  136. (1997). The deiodinase family of selenoproteins,”
  137. (2005). The effects of iodine deficiency on thyroid hormone deiodination,”
  138. (2005). The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate,”
  139. (2001). The human, but not rat, dio2 gene is stimulated by thyroid transcription
  140. (2000). The mechanism of action of thyroid hormones,”
  141. (1987). The regional hypothalamic distribution of type II
  142. (2005). The roles of the iodothyronine deiodinases in mammalian development,”
  143. (2005). The significance of thyroid hormone transporters in the brain,”
  144. (1998). The thyroid gland,” in Williams Textbook of Endocrinology,J .D .W i l s o n
  145. (2004). Third ventricular alloxan reversibly impairs glucose counterregulatory responses,”
  146. (2006). Thyroid hormone action at the cellular, genomic and target gene levels,” Molecular and Cellular Endocrinology,
  147. (2008). Thyroid hormone action in the adult brain: gene expression profiling of the effects of single and multiple doses of triiodo-Lthyronine in the rat striatum,”
  148. (1998). Thyroid hormone action on astroglial cells from distinct brain regions during development,”
  149. (2006). Thyroid hormone and astrocyte morphogenesis,”
  150. (1995). Thyroid hormone and conditioned medium effects on astroglial cells from hypothyroid and normal rat brain: factor secretion, cell differentiation, and proliferation,”
  151. (2005). Thyroid hormone deiodinases in the central and peripheral nervous system,”
  152. (1986). Thyroid hormone effects on growth and development,” in Thyroid Hormone Metabolism,
  153. (2001). Thyroid hormone induces cerebellar astrocytes and C6 glioma cells to secrete mitogenic growth factors,”
  154. (1997). Thyroid hormone induces protein secretion and morphological changes in astroglial cells with an increase in expression of glial fibrillary acidic protein,”
  155. (2003). Thyroid hormone modulates the extracellular matrix organization and expression in cerebellar astrocyte: effects on astrocyte adhesion,”
  156. (2007). Thyroid hormone receptors in brain development and function,”
  157. (2004). Thyroid hormone regulates oligodendrocyte accumulation in developing rat brain white matter tracts,”
  158. (2011). Thyroid hormone regulates the expression of the sonic hedgehog signaling pathway in the embryonic and adult mammalian brain,”
  159. Thyroid hormone transport in and out of cells,” Trends in EndocrinologyandMetabolism,vol.19,no.2,pp.50–56,2008.
  160. (2007). Thyroid hormone transporters in health and disease: advances in thyroid hormone deiodination,”
  161. (1997). Thyroid hormone-regulated actin polymerization in brain,”
  162. (2001). Thyroid hormone, neural tissue and mood modulation,” The world
  163. (2010). Thyroid hormoneregulated mouse cerebral cortex genes are differentially dependent on the source of the hormone: a study in monocarboxylate transporter-8- and deiodinase-2-deficient mice,”
  164. (1997). Thyroid hormones inhibit type 2 iodothyronine deiodinase in the rat cerebral cortex by both pre- and posttranslational mechanisms,”Endocrinology, vol.138,no.12,pp.5231–5237,
  165. (1994). Thyroid hormones, the brain, and affective disorders,”
  166. (1992). Thyroid receptors in the rat brain,”
  167. (2008). Thyrotrophin in the pars tuberalis triggers photoperiodic response,”
  168. (1992). Thyrotropinreleasing hormone gene expression in the hypothalamic paraventricular nucleus is dependent upon feedback regulation by both triiodothyronine and thyroxine,”
  169. (1990). Thyroxine-dependent m o d u l a t i o no fa c t i np o l y m e r i z a t i o ni nc u l t u r e da s t r o c y t e s . A novel, extranuclear action of thyroid hormone,”
  170. (1995). Thyroxinedependent regulation of integrin-laminin interactions in astrocytes,”
  171. (1992). Transcriptional regulation. A closer look at E2F,”
  172. (2004). Triiodothyronine stimulates food intake via the hypothalamic ventromedial nucleus independent of changes in energy expenditure,”
  173. (1985). Triiodothyronine stimulation of oligodendroglial differentiation and myelination.
  174. (1998). Twenty proteins containing a C-terminal SOCS box form five structural classes,”
  175. (1998). Type 2 iodothyronine deiodinase in rat pituitary tumor cells is inactivated in proteasomes,”
  176. (2006). Type 3 deiodinase is critical for the maturation and function of the thyroid axis,”
  177. (2002). Ubc6p and Ubc7p are required for normal and substrate-induced endoplasmic reticulumassociated degradation of the human selenoprotein type 2 iodothyronine monodeiodinase,”
  178. (2007). Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity,”
  179. (1998). Up-regulation of type 2 iodothyronine deiodinase mRNA in reactive astrocytes following traumatic brain injury in the rat,”
  180. (2008). Ze¨ o l d ,M .D e n t i c e ,D .S a l v a t o r e ,a n dA .C . Bianco, “Activation and inactivation of thyroid hormone by deiodinases:localactionwithgeneralconsequences,”Cellular and Molecular Life Sciences,