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. 1993 Jul 2;122(2):443–450. doi: 10.1083/jcb.122.2.443

Neurotrophin-3 induced by tri-iodothyronine in cerebellar granule cells promotes Purkinje cell differentiation [published erratum appears in J Cell Biol 1998 Dec 28;143(7):following 2090]

PMCID: PMC2119654  PMID: 8320266

Abstract

Thyroid hormones play an important role in brain development, but the mechanism(s) by which triiodothyronine (T3) mediates neuronal differentiation is poorly understood. Here we demonstrate that T3 regulates the neurotrophic factor, neurotrophin-3 (NT-3), in developing rat cerebellar granule cells both in cell culture and in vivo. In situ hybridization experiments showed that developing Purkinje cells do not express NT-3 mRNA but do express trkC, the putative neuronal receptor for NT-3. Addition of recombinant NT-3 to cerebellar cultures from embryonic rat brain induces hypertrophy and neurite sprouting of Purkinje cells, and upregulates the mRNA encoding the calcium-binding protein, calbindin-28 kD. The present study demonstrates a novel interaction between cerebellar granule neurons and developing Purkinje cells in which NT-3 induced by T3 in the granule cells promotes Purkinje cell differentiation.

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Selected References

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  1. Aloe L., Vigneti E. In vivo and in vitro NGF studies on developing cerebellar cells. Neuroreport. 1992 Mar;3(3):279–282. doi: 10.1097/00001756-199203000-00017. [DOI] [PubMed] [Google Scholar]
  2. Bandtlow C. E., Meyer M., Lindholm D., Spranger M., Heumann R., Thoenen H. Regional and cellular codistribution of interleukin 1 beta and nerve growth factor mRNA in the adult rat brain: possible relationship to the regulation of nerve growth factor synthesis. J Cell Biol. 1990 Oct;111(4):1701–1711. doi: 10.1083/jcb.111.4.1701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berkemeier L. R., Winslow J. W., Kaplan D. R., Nikolics K., Goeddel D. V., Rosenthal A. Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron. 1991 Nov;7(5):857–866. doi: 10.1016/0896-6273(91)90287-a. [DOI] [PubMed] [Google Scholar]
  4. Bradley D. J., Young W. S., 3rd, Weinberger C. Differential expression of alpha and beta thyroid hormone receptor genes in rat brain and pituitary. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7250–7254. doi: 10.1073/pnas.86.18.7250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brent G. A., Moore D. D., Larsen P. R. Thyroid hormone regulation of gene expression. Annu Rev Physiol. 1991;53:17–35. doi: 10.1146/annurev.ph.53.030191.000313. [DOI] [PubMed] [Google Scholar]
  6. Burgess W. H., Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem. 1989;58:575–606. doi: 10.1146/annurev.bi.58.070189.003043. [DOI] [PubMed] [Google Scholar]
  7. Burgoyne R. D., Cambray-Deakin M. A. The cellular neurobiology of neuronal development: the cerebellar granule cell. Brain Res. 1988 Jan-Mar;472(1):77–101. doi: 10.1016/0165-0173(88)90006-9. [DOI] [PubMed] [Google Scholar]
  8. Castrén E., Zafra F., Thoenen H., Lindholm D. Light regulates expression of brain-derived neurotrophic factor mRNA in rat visual cortex. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9444–9448. doi: 10.1073/pnas.89.20.9444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Cohen-Cory S., Dreyfus C. F., Black I. B. NGF and excitatory neurotransmitters regulate survival and morphogenesis of cultured cerebellar Purkinje cells. J Neurosci. 1991 Feb;11(2):462–471. doi: 10.1523/JNEUROSCI.11-02-00462.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dugich-Djordjevic M. M., Tocco G., Lapchak P. A., Pasinetti G. M., Najm I., Baudry M., Hefti F. Regionally specific and rapid increases in brain-derived neurotrophic factor messenger RNA in the adult rat brain following seizures induced by systemic administration of kainic acid. Neuroscience. 1992;47(2):303–315. doi: 10.1016/0306-4522(92)90246-x. [DOI] [PubMed] [Google Scholar]
  12. Dussault J. H., Ruel J. Thyroid hormones and brain development. Annu Rev Physiol. 1987;49:321–334. doi: 10.1146/annurev.ph.49.030187.001541. [DOI] [PubMed] [Google Scholar]
  13. Ernfors P., Ibáez C. F., Ebendal T., Olson L., Persson H. Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5454–5458. doi: 10.1073/pnas.87.14.5454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ernfors Patrik, Merlio Jean-Phillipe, Persson Håkan. Cells Expressing mRNA for Neurotrophins and their Receptors During Embryonic Rat Development. Eur J Neurosci. 1992 Oct;4(11):1140–1158. doi: 10.1111/j.1460-9568.1992.tb00141.x. [DOI] [PubMed] [Google Scholar]
  15. Gall C., Murray K., Isackson P. J. Kainic acid-induced seizures stimulate increased expression of nerve growth factor mRNA in rat hippocampus. Brain Res Mol Brain Res. 1991 Jan;9(1-2):113–123. doi: 10.1016/0169-328x(91)90136-l. [DOI] [PubMed] [Google Scholar]
  16. Glass D. J., Nye S. H., Hantzopoulos P., Macchi M. J., Squinto S. P., Goldfarb M., Yancopoulos G. D. TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor. Cell. 1991 Jul 26;66(2):405–413. doi: 10.1016/0092-8674(91)90629-d. [DOI] [PubMed] [Google Scholar]
  17. Götz R., Kolbeck R., Lottspeich F., Barde Y. A. Production and characterization of recombinant mouse neurotrophin-3. Eur J Biochem. 1992 Mar 1;204(2):745–749. doi: 10.1111/j.1432-1033.1992.tb16689.x. [DOI] [PubMed] [Google Scholar]
  18. Hallbök F., Ibáez C. F., Persson H. Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Neuron. 1991 May;6(5):845–858. doi: 10.1016/0896-6273(91)90180-8. [DOI] [PubMed] [Google Scholar]
  19. Hatten M. E., Lynch M., Rydel R. E., Sanchez J., Joseph-Silverstein J., Moscatelli D., Rifkin D. B. In vitro neurite extension by granule neurons is dependent upon astroglial-derived fibroblast growth factor. Dev Biol. 1988 Feb;125(2):280–289. doi: 10.1016/0012-1606(88)90211-4. [DOI] [PubMed] [Google Scholar]
  20. Heisenberg C. P., Thoenen H., Lindholm D. Tri-iodothyronine regulates survival and differentiation of rat cerebellar granule neurons. Neuroreport. 1992 Aug;3(8):685–688. doi: 10.1097/00001756-199208000-00008. [DOI] [PubMed] [Google Scholar]
  21. Hofer M., Pagliusi S. R., Hohn A., Leibrock J., Barde Y. A. Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J. 1990 Aug;9(8):2459–2464. doi: 10.1002/j.1460-2075.1990.tb07423.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hunziker W., Schrickel S. Rat brain calbindin D28: six domain structure and extensive amino acid homology with chicken calbindin D28. Mol Endocrinol. 1988 May;2(5):465–473. doi: 10.1210/mend-2-5-465. [DOI] [PubMed] [Google Scholar]
  23. Ip N. Y., Ibáez C. F., Nye S. H., McClain J., Jones P. F., Gies D. R., Belluscio L., Le Beau M. M., Espinosa R., 3rd, Squinto S. P. Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3060–3064. doi: 10.1073/pnas.89.7.3060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jande S. S., Maler L., Lawson D. E. Immunohistochemical mapping of vitamin D-dependent calcium-binding protein in brain. Nature. 1981 Dec 24;294(5843):765–767. doi: 10.1038/294765a0. [DOI] [PubMed] [Google Scholar]
  25. Jones K. R., Reichardt L. F. Molecular cloning of a human gene that is a member of the nerve growth factor family. Proc Natl Acad Sci U S A. 1990 Oct;87(20):8060–8064. doi: 10.1073/pnas.87.20.8060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kaisho Y., Yoshimura K., Nakahama K. Cloning and expression of a cDNA encoding a novel human neurotrophic factor. FEBS Lett. 1990 Jun 18;266(1-2):187–191. doi: 10.1016/0014-5793(90)81536-w. [DOI] [PubMed] [Google Scholar]
  27. Karns L. R., Ng S. C., Freeman J. A., Fishman M. C. Cloning of complementary DNA for GAP-43, a neuronal growth-related protein. Science. 1987 May 1;236(4801):597–600. doi: 10.1126/science.2437653. [DOI] [PubMed] [Google Scholar]
  28. Klein R., Martin-Zanca D., Barbacid M., Parada L. F. Expression of the tyrosine kinase receptor gene trkB is confined to the murine embryonic and adult nervous system. Development. 1990 Aug;109(4):845–850. doi: 10.1242/dev.109.4.845. [DOI] [PubMed] [Google Scholar]
  29. Klein R., Nanduri V., Jing S. A., Lamballe F., Tapley P., Bryant S., Cordon-Cardo C., Jones K. R., Reichardt L. F., Barbacid M. The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell. 1991 Jul 26;66(2):395–403. doi: 10.1016/0092-8674(91)90628-c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lamballe F., Klein R., Barbacid M. trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell. 1991 Sep 6;66(5):967–979. doi: 10.1016/0092-8674(91)90442-2. [DOI] [PubMed] [Google Scholar]
  31. 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(6):382–396. doi: 10.1159/000112189. [DOI] [PubMed] [Google Scholar]
  32. Leibrock J., Lottspeich F., Hohn A., Hofer M., Hengerer B., Masiakowski P., Thoenen H., Barde Y. A. Molecular cloning and expression of brain-derived neurotrophic factor. Nature. 1989 Sep 14;341(6238):149–152. doi: 10.1038/341149a0. [DOI] [PubMed] [Google Scholar]
  33. Levi-Montalcini R., Angeletti P. U. Nerve growth factor. Physiol Rev. 1968 Jul;48(3):534–569. doi: 10.1152/physrev.1968.48.3.534. [DOI] [PubMed] [Google Scholar]
  34. Lindholm D. B. Thyroxine regulates the activity and the concentration of synaptic plasma membrane Na,K-ATPase in the developing rat brain cortex. Brain Res. 1984 Jul;317(1):83–88. doi: 10.1016/0165-3806(84)90142-1. [DOI] [PubMed] [Google Scholar]
  35. Lindholm D., Castrén E., Kiefer R., Zafra F., Thoenen H. Transforming growth factor-beta 1 in the rat brain: increase after injury and inhibition of astrocyte proliferation. J Cell Biol. 1992 Apr;117(2):395–400. doi: 10.1083/jcb.117.2.395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lu B., Yokoyama M., Dreyfus C. F., Black I. B. Depolarizing stimuli regulate nerve growth factor gene expression in cultured hippocampal neurons. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6289–6292. doi: 10.1073/pnas.88.14.6289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Maisonpierre P. C., Belluscio L., Friedman B., Alderson R. F., Wiegand S. J., Furth M. E., Lindsay R. M., Yancopoulos G. D. NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron. 1990 Oct;5(4):501–509. doi: 10.1016/0896-6273(90)90089-x. [DOI] [PubMed] [Google Scholar]
  38. Maisonpierre P. C., Belluscio L., Squinto S., Ip N. Y., Furth M. E., Lindsay R. M., Yancopoulos G. D. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science. 1990 Mar 23;247(4949 Pt 1):1446–1451. doi: 10.1126/science.247.4949.1446. [DOI] [PubMed] [Google Scholar]
  39. Mellström B., Naranjo J. R., Santos A., Gonzalez A. M., Bernal J. Independent expression of the alpha and beta c-erbA genes in developing rat brain. Mol Endocrinol. 1991 Sep;5(9):1339–1350. doi: 10.1210/mend-5-9-1339. [DOI] [PubMed] [Google Scholar]
  40. Nicholson J. L., Altman J. The effects of early hypo- and hyperthyroidism on the development of rat cerebellar cortex. I. Cell proliferation and differentiation. Brain Res. 1972 Sep 15;44(1):13–23. doi: 10.1016/0006-8993(72)90362-9. [DOI] [PubMed] [Google Scholar]
  41. Pioro E. P., Cuello A. C. Purkinje cells of adult rat cerebellum express nerve growth factor receptor immunoreactivity: light microscopic observations. Brain Res. 1988 Jul 5;455(1):182–186. doi: 10.1016/0006-8993(88)90131-x. [DOI] [PubMed] [Google Scholar]
  42. Rocamora N., García-Ladona F. J., Palacios J. M., Mengod G. Differential expression of brain-derived neurotrophic factor, neurotrophin-3, and low-affinity nerve growth factor receptor during the postnatal development of the rat cerebellar system. Brain Res Mol Brain Res. 1993 Jan;17(1-2):1–8. doi: 10.1016/0169-328x(93)90065-w. [DOI] [PubMed] [Google Scholar]
  43. Rosenthal A., Goeddel D. V., Nguyen T., Lewis M., Shih A., Laramee G. R., Nikolics K., Winslow J. W. Primary structure and biological activity of a novel human neurotrophic factor. Neuron. 1990 May;4(5):767–773. doi: 10.1016/0896-6273(90)90203-r. [DOI] [PubMed] [Google Scholar]
  44. Samuels H. H., Forman B. M., Horowitz Z. D., Ye Z. S. Regulation of gene expression by thyroid hormone. J Clin Invest. 1988 Apr;81(4):957–967. doi: 10.1172/JCI113449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sap J., Muñoz A., Damm K., Goldberg Y., Ghysdael J., Leutz A., Beug H., Vennström B. The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature. 1986 Dec 18;324(6098):635–640. doi: 10.1038/324635a0. [DOI] [PubMed] [Google Scholar]
  46. Soppet D., Escandon E., Maragos J., Middlemas D. S., Reid S. W., Blair J., Burton L. E., Stanton B. R., Kaplan D. R., Hunter T. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell. 1991 May 31;65(5):895–903. doi: 10.1016/0092-8674(91)90396-g. [DOI] [PubMed] [Google Scholar]
  47. Squinto S. P., Stitt T. N., Aldrich T. H., Davis S., Bianco S. M., Radziejewski C., Glass D. J., Masiakowski P., Furth M. E., Valenzuela D. M. trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor. Cell. 1991 May 31;65(5):885–893. doi: 10.1016/0092-8674(91)90395-F. [DOI] [PubMed] [Google Scholar]
  48. Strait K. A., Schwartz H. L., Seybold V. S., Ling N. C., Oppenheimer J. H. Immunofluorescence localization of thyroid hormone receptor protein beta 1 and variant alpha 2 in selected tissues: cerebellar Purkinje cells as a model for beta 1 receptor-mediated developmental effects of thyroid hormone in brain. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3887–3891. doi: 10.1073/pnas.88.9.3887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Stübner D., Gärtner R., Greil W., Gropper K., Brabant G., Permanetter W., Horn K., Pickardt C. R. Hypertrophy and hyperplasia during goitre growth and involution in rats--separate bioeffects of TSH and iodine. Acta Endocrinol (Copenh) 1987 Dec;116(4):537–548. doi: 10.1530/acta.0.1160537. [DOI] [PubMed] [Google Scholar]
  50. Thoenen H., Barde Y. A. Physiology of nerve growth factor. Physiol Rev. 1980 Oct;60(4):1284–1335. doi: 10.1152/physrev.1980.60.4.1284. [DOI] [PubMed] [Google Scholar]
  51. Thompson C. C., Weinberger C., Lebo R., Evans R. M. Identification of a novel thyroid hormone receptor expressed in the mammalian central nervous system. Science. 1987 Sep 25;237(4822):1610–1614. doi: 10.1126/science.3629259. [DOI] [PubMed] [Google Scholar]
  52. Umesono K., Giguere V., Glass C. K., Rosenfeld M. G., Evans R. M. Retinoic acid and thyroid hormone induce gene expression through a common responsive element. Nature. 1988 Nov 17;336(6196):262–265. doi: 10.1038/336262a0. [DOI] [PubMed] [Google Scholar]
  53. Weinberger C., Thompson C. C., Ong E. S., Lebo R., Gruol D. J., Evans R. M. The c-erb-A gene encodes a thyroid hormone receptor. Nature. 1986 Dec 18;324(6098):641–646. doi: 10.1038/324641a0. [DOI] [PubMed] [Google Scholar]
  54. Yeh H. J., Ruit K. G., Wang Y. X., Parks W. C., Snider W. D., Deuel T. F. PDGF A-chain gene is expressed by mammalian neurons during development and in maturity. Cell. 1991 Jan 11;64(1):209–216. doi: 10.1016/0092-8674(91)90222-k. [DOI] [PubMed] [Google Scholar]
  55. Zafra F., Castrén E., Thoenen H., Lindholm D. Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10037–10041. doi: 10.1073/pnas.88.22.10037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Zafra F., Hengerer B., Leibrock J., Thoenen H., Lindholm D. Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J. 1990 Nov;9(11):3545–3550. doi: 10.1002/j.1460-2075.1990.tb07564.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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