Skip to main content
SpringerLink
Log in

Impact of thyroid hormone deficiency on the developing CNS: cerebellar glial and neuronal protein expression in rat neonates exposed to antithyroid drug propylthiouracil

  • Scientific Papers
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

The developing rat cerebellum is vulnerable to thyroid hormone (TH) deficiency. The present study addresses the molecular mechanisms involved in this response. Specifically, the study focuses on the expression of selected cerebellar proteins that are known to be directly [protein expressing 3-fucosyl-N-acetyl-lactosamine antigen (CD15), neuronal cell adhesion molecule (L1)] or indirectly [glial fibrillary acidic protein (GFAP)], involved in glial-neuronal interactions and thus regulation of cell proliferation and granule cell migration. Cerebellar mass, structure, and protein expression in rat neonates exposed to antithyroid drug propylthiouracil (PTU) from the embryonic day (E) 16 to postnatal day (P) 21 were compared against rat neonates that received replacement of thyroxin (T4) starting on day P1 or untreated controls. Cerebellar proteins were analyzed by quantitative Western blots. PTU-treated rats lagged in growth and showed reduction in cerebellar mass and alterations in cerebellar structure on P15. Daily treatment of neonates with T4 restored normal cerebellum-to-body-mass ratio, cerebellar structure, and cerebellar protein expression. Densitometric analysis of Western blots revealed altered expression of selected proteins in the cerebella of hypothyroid neonates. A decrease of CD15 (46%, p = 0.031) was observed on P10 and was accompanied by a decrease in GFAP expression (64%, p= 0.039). Furthermore, a shift in the developmental GFAP profile was observed in the PTU-treated cerebellum. L1 expression was not significantly affected in the hypothyroid cerebellum. Altered expression of cerebellar proteins is likely to affect cell-cell interactions and consequently cell proliferation and migration and contribute to structural and functional alterations seen in the hypothyroid rat neonates.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Nicholson JL, Altman J. The effect of early hypo- and hyperthyroidism on the development of rat cerebellar cortex. I. Cell proliferation and differentiation. Brain Res 1972; 44: 13–23.

    Article  PubMed  CAS  Google Scholar 

  2. Oppenheimer JH, Schwartz HL. Molecular basis of thyroid hormone-dependent brain development. Endocrine Rev 1997; 18: 462–475.

    Article  CAS  Google Scholar 

  3. DeLong GR, Stanbury JB, Fierro-Benitez R. Neurological signs in congenital iodine-deficiency disorder (endemic cretinism). Dev Med Child Neurol 1985; 27: 317–324.

    Article  PubMed  CAS  Google Scholar 

  4. Porterfield SP, Hendrich CE. The role of thyroid hormones in prenatal and neonatal development current perspectives. Endocr Rev 1993; 14: 94–106.

    Article  PubMed  CAS  Google Scholar 

  5. Alvarez M, Guell R, Daniel L, Berazain AR, Machado C, Pascual A. Neurocognitive condition of 8 year old children with congenital hypothyroidism treated early. Rev Neurol 1999; 28: 701–706.

    PubMed  CAS  Google Scholar 

  6. Legrand J. Morphogenetic actions of thyroid hormone. Trends Neurosci 1979; 2: 234–236.

    Article  Google Scholar 

  7. Nathaniel EJ, Nathaniel DR, Nathaniel LM, Burt S, Panfili F. Effect of thyroxine replacement therapy on the growth patterns of body, brain, cerebellum in the neonatal hypothyroid rat. Exp Neurol 1988; 101: 1–16.

    Article  PubMed  CAS  Google Scholar 

  8. Legrand C, Clos J. Biochemical, immunocytochemical and morphological evidence for an interaction between thyroid hormone and nerve growth factor in the developing cerebellum of normal and hypothyroid rats. Dev Neurosci 1991; 13: 382–396.

    Article  PubMed  CAS  Google Scholar 

  9. Vermiglio F, Sidoti M, Finocchiaro MD, et al. Defective neuromotor and cognitive ability in iodine-deficient schoolchildren of an endemic goiter region of Sicily. J Clin Endocrinol Metab 1990; 70: 379–384.

    PubMed  CAS  Google Scholar 

  10. Timmann D, Horak FB. Perturbed step initiation in cerebellar subjects: 2. Modification of anticipatory postural adjustments. Exp Brain Res 2001; 141: 110–120.

    Article  PubMed  CAS  Google Scholar 

  11. Rabie A, Favre C, Clavel MC, Legrand J. Sequential effects of thyroxine on the developing cerebellum of rats made hypothyroid by propylthiouracil. Brain Res 1979; 161: 469–479.

    Article  PubMed  CAS  Google Scholar 

  12. Hatten ME. Neuronal inhibition of astroglial cell proliferation is membrane mediated. J Cell Biol 1987; 104: 1353–1360.

    Article  PubMed  CAS  Google Scholar 

  13. Koibuchi N, Matsuzaki S, Ichimura K, Ohtake H, Yamaoka S. Effect of perinatal hypothyroidism on expression of cytochrome oxidase subunit I gene, which is clone by differential plaque screening from the cerebellum of newborn rat. J Neuroendocrinol 1995; 7: 847–853.

    Article  PubMed  CAS  Google Scholar 

  14. Sajdel-Sulkowska ES, Koibuchi N. Altered CD15 glycolipid expression in the developing rat cerebullum following treatment with antithyroid drug, propylthiouracil. Endocr J 2000; 47: 353–358.

    Article  PubMed  CAS  Google Scholar 

  15. Hendelman WJ. Dissection guide for cerebellum Locus Coruleus organotypic cultures. In: Shahar A, de Vellis J, Vernadakis A, Haber B. A Dissection and Tissue Culture Manual of the Nervous System. New York, NY: Alan R. Liss, Inc., 1990: 16–22

    Google Scholar 

  16. Margolis RK, Rauch U, Maurel P, Margolis RU. Neurocan and phosphocan: two major nervous tissue-specific chondroitin sulfate proteoglycans. Prospect Dev Neurobiol 1996; 3: 273–290

    CAS  Google Scholar 

  17. Condorelli DF, Nicoletti VG, Barresi V, et al. Structural features of the rat GFAP gene and identification of a novel alternative transcript. J Neurosci. Res. 1999; 56: 219–228

    Article  PubMed  CAS  Google Scholar 

  18. Patel AJ, Rabie A, Lewis PD, Balazs R. Effect of thyroid deficiency on postnatal cell formation in the rat brain: a biochemical investigation. Brain Res 1976; 104: 33–46

    Article  PubMed  CAS  Google Scholar 

  19. Faivre-Sarrailh C, Rami A, Fages C, Tardy M. Effect of thyroid deficiency on glial fibrillary acidic protein (GFAP) and GFAP-mRNA in the cerebellum and hippocampal formation of the developing rat. Glia 1991; 4: 276–284

    Article  PubMed  CAS  Google Scholar 

  20. Farwell AP, Dubord-Tomasetti SA. Thyroid hormone regulates the expression of laminin in the developing rat cerebellum. Endocrinology 1999; 140: 4221–4227

    Article  PubMed  CAS  Google Scholar 

  21. Lagenaur C, Schachner M, Solter D, Knowles B. Monoclonal antibody against SSEA-1 is specific for subpopulation of astrocytes in mouse cerebellum. Neurosci Lett 1982; 31: 181–184

    Article  PubMed  CAS  Google Scholar 

  22. Niedieck B, Lohler J. Expression of 3-fucosyl-N-acetyllactos-amine on glial cells and its putative role in cell adhesion. Acta Neuropathol 1987; 75: 173–184

    Article  PubMed  CAS  Google Scholar 

  23. Gocht A, Struckhoff G, Lohler J. The carbohydrate epitope — fucosyl-N-acetyllactosamine is region-specifically expressed in astrocytes of the rat brain. Light- and electon-microscopical observations. Acta Anat 1994; 150: 205–216

    Article  PubMed  CAS  Google Scholar 

  24. Sajdel-Sulkowska EM. Immunofluorescent detection of CD15-fucosylated glycoconjugates in primary cultures and their function in glial-neuronal adhesion. Acta Polonica 1998; 45: 781–790

    CAS  Google Scholar 

  25. Yamamoto M, Boyer AM, Schwarting GA. Fucose-containing glycolipids are stage- and region-specific antigens in developing embryonic brain of rodents. Proc Natl Acad Sci USA 1985; 82 3045–3049.

    Article  PubMed  CAS  Google Scholar 

  26. Schonlau C, Mai JK. Age-related expression of the CD15 (— fucosyl-N-acetyl-lactosamine) epitope in the monkey (Cercopithecus aethiops aethiops L.) lateral geniculate nucleus. Eur JMorphol 1995; 33: 119–128.

    CAS  Google Scholar 

  27. Feizi T. Carbohydrate differentiation antigens probable ligands for cell adhesion molecules. Trends Bio Sci 1991; 16: 84–86.

    Article  CAS  Google Scholar 

  28. Marani E, Mai K. Expression of the carbohydrate epitope — fucosyl-Nacetyllactosamine (CD15) in the veterbrate cerebellar cortex. Histochem J 1992; 24: 852–868.

    Article  PubMed  CAS  Google Scholar 

  29. Landry CF, Ivy GO, Brown IR. Developmental expression of glial fibrillary acidic protein mRNA in the rat brain analyzed by in situ hybridization. J. Neurosci. Res. 1990; 25: 194–203.

    Article  PubMed  CAS  Google Scholar 

  30. Garcia SJ, Scidler FJ, Qiao D, Slotkin TA. Chlorpyrifos targets developing glia: effects on glial fibrillary protein. Brain Res Dev Brain Res 2002; 133: 151–161.

    Article  PubMed  CAS  Google Scholar 

  31. Clos J, Legrand J, Ghandour MS, Labourdette G, Vincendon G, Gombbos G. Effect of thyroid state and undernutrition on S100 protein and astroglia development in rat cerebellum. Dev Neurosci 1982; 5: 285–292.

    Article  PubMed  CAS  Google Scholar 

  32. Aizenman Y, de Vellis J. Synergistic action of thyroid hormone, insulin and hydrocortisone on astrocyte differentiation. Brain Res 1987; 414: 301–308.

    Article  PubMed  CAS  Google Scholar 

  33. Kettenmann H, Wienrich M, Schachner M. Neurosci Lett 1983; 41: 85–90.

    Article  PubMed  CAS  Google Scholar 

  34. Ignelzi MA, Jr, Miller DR, Soriano P, Maness PF. Impaired neurite outgrowth of src-minus cerebellar neurons on the cell adhesion molecule L1. Neuron 1994; 12: 873–884.

    Article  PubMed  CAS  Google Scholar 

  35. ThelenK, KedarV, Panicker AK, Schmid RS,Midkiff BR, Maness PF. The neuronal cell adhesion molecule L1 potentiates integrindependent cell migration to extracellular matrix proteins. J Neurosci 2002; 22: 4918–4931.

    Google Scholar 

  36. Asou H, Miura M, Kobayashi M, Uyemura K. The cell adhesion molecule L1 has specific role in neural cell migration. Neuroreport 1992; 3: 481–484.

    Article  PubMed  CAS  Google Scholar 

  37. Matsumoto-Miyai K, Ninomiya A, Yamasaki H, Tamura H, Nakamura Y, Shiosaka S. J Neurosci 2003; 23: 7727–7736.

    PubMed  CAS  Google Scholar 

  38. Liljelund P, Ghosh P, van den Pol AN. Expression of the neuronal molecule L1 in the developing and adult rat brain. J Biol Chem 1994; 268: 32886–32895.

    Google Scholar 

  39. Linnemann D, Edvardsen K, Bock E. Developmental study of the cell adhesion molecule L1. Dev Neurosci 1988; 10: 34–42.

    Article  PubMed  CAS  Google Scholar 

  40. Rathjen FG, Schachner M. Immunocytochemical and biochemical characterization of a new neuronal cell surface component (L1 antigen) which is involved in cell adhesion. EMBO 1984; 3: 1–10.

    CAS  Google Scholar 

  41. Alvarez-Dolado M, Cuadrado A, Navarro-Yubero C, Sonderegger P, Furley AJ, Bernai J, Munoz A. Regulation of the Li Cell adhesion molecule by thyroid hormone in the developing brain. Mol Cell Neurosci 2000; 16: 499–514.

    Article  PubMed  CAS  Google Scholar 

  42. Garcia-Segura LM, Chowen JA, Naftolin F. Endocrine glia: roles of glial cells in the brain actions of steroid and thyroid hormones and in regulation of hormone secretion. Front. Neuroendocrinol. 1996; 17: 180–211.

    Article  PubMed  CAS  Google Scholar 

  43. Harvey CB, Williams GR. Mechanism of thyroid hormone action. Thyroid 2002; 12: 441–446.

    Article  PubMed  CAS  Google Scholar 

  44. Lazar MA. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 1993; 14: 184–193.

    Article  PubMed  CAS  Google Scholar 

  45. Moura Neto V, Trentin A, Lima F, Gomes F, Goncalves N, Chamas LV, Lins C, Garcia-Abreu J, Rosenthal D, Chagas C. Effects (correction of effects) on the thyroid hormone (T3) on astrocytes. Rev Bras Biol 1996; 56 Su. 1 Pt.: 123–134.

    Google Scholar 

  46. Lebel JM, L’Herault S, Dussault JH, Puymirat J. Thyroid hormone up-regulates thyroid hormone receptor beta gene expression in rat cerebral hemisphere astrocyte cultures. Glia 1993; 9: 105–112.

    Article  PubMed  CAS  Google Scholar 

  47. Puymirat J, Miehe M, Marchand R, Sarlieve L, Dussault JH. Immunocytochemical localization of thyroid hormone receptors in the adult rat brain. Thyroid 1991; 1: 173–184.

    Article  PubMed  CAS  Google Scholar 

  48. Carlson DJ, Strait KA, Schwartz HL, Oppenheimer JH. (1994) Immunofluorescent localization of thyroid hormone receptor isoforms in glial cells of rat brain. Endocrinology 1994; 135: 1831–1836.

    Article  PubMed  CAS  Google Scholar 

  49. Leonard JC, Farwell AP, Yen PM, Chin WW, Stula M. Differential expression of thyroid hormone receptor isoforms in neurons and astroglial cells. Endocrinology 1994; 135: 548–555.

    Article  PubMed  CAS  Google Scholar 

  50. Davis PJ, Davis FB. Nongenomic actions of thyroid hormone. In: Braverman LE. Diseases of the Thyroid. Totawa, N.J: Humana Press, 1997: 17–34.

    Google Scholar 

  51. Trentin AG, De Aguiar CB, Garcez RC, Alvarez-Silva M. Thyroid hormone modulates the extracellular matrix organization and expression in cerebellar astrocytes: effects on astrocyte adhesion. Glia 2003; 42: 359–369.

    Article  PubMed  Google Scholar 

  52. Edmundson JC, Hatten ME. Glial-guided granule neuron migration in vitro: a high-resolution time-lapse video microscopic study. J Neurosci 1987; 7: 1928–19340.

    Google Scholar 

  53. Alvarez-Dolado M, Gonzalez Sancho JM, Bernai J, Munoz A. Developmental expression of tenascin-C is altered by hypothyroidism in the rat brain. Neurosci 1998; 84: 309–322.

    Article  CAS  Google Scholar 

  54. Alvarez-Dolado M, Ruiz M, Del Rio JA, et al. Thyroid hormone regulates reelin and dabl expression during brain development. J Neurosci 1999; 19: 6979–6993.

    PubMed  CAS  Google Scholar 

  55. Konig S, Moura Neto V. Thyroid hormone action on neuronal cells. Cell Mol Neurobiol 2002; 22: 517–544.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts, USA

    Gui-Hua Li, Jennifer Post & Elizabeth M. Sajdel-Sulkowska

  2. Department of Integrative Physiology and CREST, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

    Noriyuki Koibuchi

  3. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA

    Elizabeth M. Sajdel-Sulkowska

Authors
  1. Gui-Hua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer Post
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noriyuki Koibuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elizabeth M. Sajdel-Sulkowska
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elizabeth M. Sajdel-Sulkowska.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, GH., Post, J., Koibuchi, N. et al. Impact of thyroid hormone deficiency on the developing CNS: cerebellar glial and neuronal protein expression in rat neonates exposed to antithyroid drug propylthiouracil. The Cerebellum 3, 100–106 (2004). https://doi.org/10.1080/14734220410029650

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1080/14734220410029650

Keywords

Search

Navigation