Regulation of Type III Intermediate Filament Protein Genes in Astrocytes during Development and after Injury

  • Monica M. Oblinger
  • Susanne A. Kost
  • Leelabai D. Singh
Part of the Altschul Symposia Series book series (ALSS, volume 2)


Intermediate filaments (IFs) represent the major proportion of the cytoskeletal framework in astrocytes, as well as in most other eukaryotic cells, and thus, the regulation of IF gene expression is central in determining important aspects of astrocyte form and function. Of interest are the significant transitions in IF expression that occur in astrocytes during development and in pathological conditions. These transitions have been the focus of extensive study and it is widely understood that, while mature astrocytes have an IF cytoskeleton dominated by glial fibrillary acidic protein (GFAP), astrocytes at earlier developmental stages elaborate a vimentin-dominated IF cytoskeleton. When astrocytes become reactive after a traumatizing injury to the CNS they substantially upregulate expression of both GFAP and vimentin, an event which spawns dramatic morphological changes in the reactive astrocytes. Such transformations of the IF cytoskeleton in astrocytes are the result of complex interactions between environmental and genomic factors that are only beginning to be explored. The present paper will review some recent information concerning IF expression in astrocytes and its regulation and also consider the functional consequences of transitions between vimentin vs. GFAP-dominated cytoskeletal structure in developing and reactive astrocytes. Since a number of excellent and comprehensive reviews about GFAP in mature as well as in reactive astrocytes exist (Chiu and Goldman, 1985; Eng, 1985; Eng, 1988; Eng and Shiurba, 1988; Reier, et al., 1989), the present paper aims only to supplement information extant in this broad field.


Glial Fibrillary Acidic Protein Corticospinal Tract Reactive Astrocyte Wallerian Degeneration Reactive Astrogliosis 


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  1. Angevine, J.B.J., and Sidman, R.L., 1961, Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse, Nature 192: 766.PubMedCrossRefGoogle Scholar
  2. Aquino, D.A., Chiu, F.C., Brosnan, C.F., and Norton, W.T., 1988, Glial fibrillary acidic protein increases in the spinal cord of Lewis rats with acute experimental autoimmune encephalomyelitis, J. Neurochem. 51: 1085.PubMedCrossRefGoogle Scholar
  3. Aquino, D.A., Shafit-Zagardo, B., Brosnan, C.F., and Norton, W.T., 1990, Expression of glial fibrillary acidic protein and neurofilament mRNA in gliosis induced by experimental autoimmune encephalomyelitis, J. Neurochem. 54: 1398.PubMedCrossRefGoogle Scholar
  4. Bayer, S.A., 1985, The development of the central nervous system, in: “Developmental Neurochemistry”, R. Wiggins, D. McCandless and S. Enna, ed., University of Texas Press, Austin, TX.Google Scholar
  5. Bignami, A., and Dahl, D., 1974, Astrocyte-specific protein and radial glia in the cerebral cortex of newborn rat, Nature 252: 55.PubMedCrossRefGoogle Scholar
  6. Bignami, A., and Dahl, D., 1976, The astroglial response to stabbing. Immunofluorescence studies with antibodies to astrocyte-specific protein (GFA) in mammalian and submammalian vertebrates, Neuropathol. Appl. Neurobiol. 2: 99.CrossRefGoogle Scholar
  7. Bignami, A., Raju, T., and Dahl, D., 1982, Localization of vimentin, the nonspecific intermediate filament protein, in embryonal glia and in early differentiating neurons, Dev. Biol. 91: 286.PubMedCrossRefGoogle Scholar
  8. Chiu, F.-C., and Goldman, J.E., 1984, Synthesis and turnover of cytoskeletal proteins in cultured astrocytes, J. Neurochem. 42: 166.PubMedCrossRefGoogle Scholar
  9. Chiu, F.-C., and Goldman, J.E., 1985, Regulation of glial fibrillary acidic protein (GFAP) expression in CNS development and in pathologic states, J. Neuroimmunol. 8: 283.PubMedCrossRefGoogle Scholar
  10. Cochard, P., and Paulin, D., 1984, Initial expression of neurofilaments and vimentin in the central and peripheral nervous system of the mouse embryo in vivo. J. Neurosci. 4: 2080.Google Scholar
  11. Condorelli, D.F., Dell’Albani, P., Kaczmarek, L., Messina, L., Spampinato, G., Avola, R., Messina, A., and Giuffrida Stella, A.M., 1990, Glial fibrillary acidic protein messenger RNA and glutamine synthetase activity after nervous system injury, J. Neurosci. Res. 26: 251.PubMedCrossRefGoogle Scholar
  12. Dahl, D., Bignami, A., Weber, K., and Osborn, M., 1981, Filament proteins in rat optic nerves undergoing Wallerian degeneration: localization of vimentin, the fibroblastic 100 A filament protein in normal and reactive astrocytes, Exp. Neurol. 73: 496.PubMedCrossRefGoogle Scholar
  13. Dahl, D., Rueger, D.C., Bignami, A., Weber, K., and Osbom, M., 1981, Vimentin, the 57,000 dalton protein of fibroblast filaments, is the major cytoskeletal component in immature glia, Eur. J. Cell BioL 24: 191.PubMedGoogle Scholar
  14. DeArmond, S.J., Lee, Y.-L.L., Kertzschmar, H.A., and Eng, L.F., 1986, Turnover of glial filaments in mouse spinal cord, J. Neurochem. 47: 1749.PubMedCrossRefGoogle Scholar
  15. Eisenfield, A.J., Bunt-Milam, A.H., and Sarthy, P.V., 1984, Mueller cell expression of glial fibrillary acidic protein after genetic and experimental photoreceptor degeneration in the rat retina, Invest. Ophthalmol. Vis. Sci. 25: 1321.Google Scholar
  16. Eng, L.F., 1985, Glial fibrillary acidic protein: the major protein of glial intermediate filaments in differentiated astrocytes, J. Neuroimmunol. 8: 203.PubMedCrossRefGoogle Scholar
  17. Eng, L.F., 1988, Astrocytic response to injury, in: “Current Issues in Neural Regeneration Research”, P.J. Reier, R.P. Bunge and F.J. Seil, eds., Alan R. Liss, New York.Google Scholar
  18. Eng, L.F., D’Amelio, F.E., and Smith, M.E., 1989, Dissociation of GFAP intermediate filaments in EAE: observations in the lumbar spinal cord, Glia 2: 308.PubMedCrossRefGoogle Scholar
  19. Eng, L.F., and Shiurba, R.A., 1988, Glial fibrillary acidic protein: A review of structure, function and application., in: “Neuronal and Glial Proteins: Structure, Function and Clinical Application”, P.J. Marangos, I.C. Campbell, and R.M. Cohen, eds., Academic Press, San Diego.Google Scholar
  20. Fedoroff, S., McAuley, W.A.J., Houle, J.D., and Devon, R.M., 1984, Astrocyte cell lineage. V. Similarity of astrocytes that form in the presence of dBcAMP in cultures to reactive astrocytes in vivo, J. Neurosci. Res. 12: 15.CrossRefGoogle Scholar
  21. Gilmore, S., Sims, T.J., and Leiting, J.E., 1990, Astrocyte reactions in spinal grey matter following sciatic axotomy, Glia 3: 342.PubMedCrossRefGoogle Scholar
  22. Giulian, D., Woodward, J., Young, D.G., Krebs, J.F., and Lachman, L.B., 1988, Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization, J. Neurosci. 8: 2485.PubMedGoogle Scholar
  23. Goldman, J.E., and Chiu, F., 1984, Dibutyryl cyclic AMP causes intermediate filament accumulation and actin reorganization in astrocytes, Brain Res. 306: 85.PubMedCrossRefGoogle Scholar
  24. Goss, J.R., Finch, C.E., and Morgan, D.G., 1991, Age-related changes in glial fibrillary acidic protein mRNA in the mouse brain, Neurobiol. Aging 12: 165.PubMedCrossRefGoogle Scholar
  25. Hommes, O.R., and Leblond, C.P., 1967, Mitotic division of neuroglia in the normal adult rat, J. Comp. Neurol. 129: 269.PubMedCrossRefGoogle Scholar
  26. Hozumi, I., Aquino, D.A., and Norton, W.T., 1990, GFAP mRNA levels following stab wounds in rat brain, Brain Res. 534: 291.PubMedCrossRefGoogle Scholar
  27. Janeczko, K., 1988, The proliferative response of astrocytes to injury in neonatal rat brain. A combined immunocytochemical and autoradiographic study, Brain Res. 456: 280.PubMedCrossRefGoogle Scholar
  28. Kost, S.A., Chacko, K., and Oblinger, M.M., 1992, Developmental patterns of intermediate filament gene expression in the hamster brain, Mol. Brain Res. in pressGoogle Scholar
  29. Kost-Mikucki, S.A., and Oblinger, M.M., 1991, Changes in glial fibrillary acidic protein mRNA expression after corticospinal axotomy in the adult hamster, J. Neurosci. Res. 28: 182.PubMedCrossRefGoogle Scholar
  30. Landry, C.F., Ivy, G.O., and Brown, I.R., 1990, Developmental expression of glial fibrillary acidic protein mRNA in the rat brain analyzed by in situ hybridization, J. Neurosci. Res. 25: 194.PubMedCrossRefGoogle Scholar
  31. LePrince, G., Copin, M.-C., Hardin, H., Belin, M.-F., Bouilloux, J.-P., and Tardy, M., 1990, Neuron-glia interactions: effect of serotonin on the astroglial expression of GFAP and of its encoding message, Dev. Brain Res. 51: 295.CrossRefGoogle Scholar
  32. LePrince, G., Gages, C., Nunez, R.J., and Tardy, M., 1991, DBcAMP effect on the expression of GFAP and its encoding mRNA in astroglial primary cultures, Glia 4: 322.CrossRefGoogle Scholar
  33. LeVine, S.M., and Goldman, J.E., 1988, Embryonic divergence of oligodendrocyte and astrocyte lineages in developing rat cerebrum, J. Neurosci. 8: 3992.PubMedGoogle Scholar
  34. Lewis, S.A., Balcarek, J.M., Krek, V., Shelanski, M., and Cowan, N.J., 1984, Sequence of a cDNA clone encoding mouse glial fibrillary acidic protein: Structural conservation of intermediate filaments, Proc. Nat. Acad. Sci. USA 81: 2743.PubMedCrossRefGoogle Scholar
  35. Lewis, S.A., and Cowan, N.J., 1985, Temporal expression of mouse glial fibrillary acidic protein mRNA studied by a rapid in situ hybridization procedure, J. Neurochem. 45: 913.PubMedCrossRefGoogle Scholar
  36. Malloch, G.D.A., Clark, J.B., and Burnet, F.R., 1987, Glial fibrillary acidic protein in the cytoskeletal and soluble protein fractions of the developing rat brain, J. Neurochem. 723–730.Google Scholar
  37. Merrill, J.E., 1991, Effects of interleukin-1 and tumor necrosis factor-a on astrocytes, microglia, oligodendrocytes and glial precursors in vitro, Dev. Neurosci. 13: 130.PubMedCrossRefGoogle Scholar
  38. Mikucki, S. A., and Oblinger, M.M., 1991, Vimentin mRNA expression increases after corticospinal axotomy in the adult hamster, Metab. Brain Dis. 6: 33.PubMedCrossRefGoogle Scholar
  39. Miller, R.H., Abney, E.R., S., D., ffrench-Constant, C., Lindsay, R., Patel, R., Stone, J., and Raff, M.C., 1986, Is reactive gliosis a property of a distinct population of astrocytes?, J. Neurosci. 6: 22.Google Scholar
  40. Morrison, R.S., De Vellis, J., Lee, Y.L., Bradshaw, R.A., and Eng, L.F., 1985, Hormones and growth factors induce the synthesis of glial fibrillary acidic protein in rat astrocytes, J. Neurosci. Res. 14: 167.PubMedCrossRefGoogle Scholar
  41. Nichols, N.R., Osterburg, H.H., Masters, J.N., Millar, S.L., and Finch, C.E., 1990, Messenger RNA for glial fibrillary acidic protein is decreased in rat brain following acute and chronic corticosterone treatment, Mol. Brain Res. 7: 1.PubMedCrossRefGoogle Scholar
  42. O’Callaghan, J.P., Brinton, R.E., and McEwen, B.S., 1991, Glucocorticoids regulate the synthesis of glial fibrillary acidic protein in intact and adrenalectomized rats but do not affect its expression following brain injury, J. Neurochem. 57: 860.PubMedCrossRefGoogle Scholar
  43. O’Callaghan, J.P., and Miller, D.B., 1991, The concentration of glial fibrillary acidic protein increases with age in the mouse and rat brain, Neurobiol. Aging 12: 171.PubMedCrossRefGoogle Scholar
  44. O’Callaghan, J.P., Miller, D.B., and Reinhard, J.F.J., 1990, Characterization of the origins of astrocyte response to injury using the dopaminergic neurotoxicant, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine, Brain Res. 521: 73.PubMedCrossRefGoogle Scholar
  45. Oblinger, M.M., and Singh, L., 1992, Reactive astrocytes in neonate brain upregulate intermediate filament gene expression in response to injury, Int. J. Dev. Neurobiol. in press.Google Scholar
  46. Osborn, M., and Weber, K., 1982, Intermediate filaments: Cell-type specific markers in differentiation and pathology, Cell 31: 303.PubMedCrossRefGoogle Scholar
  47. Pixley, S.A., and DeVellis, J., 1984, Transition between immature radial glia and mature astrocytes studied with a monoclonal antibody to vimentin, Dev. Brain Res. 15: 201.CrossRefGoogle Scholar
  48. Poirier, J., May, P.C., Ostemburg, H.H., Geddes, J., Cotman, C., and Finch, C.E., 1990, Selective alterations of RNA after entorhinal cortex lesioning, Proc. Nat. Acad. Sci. USA 87: 303.PubMedCrossRefGoogle Scholar
  49. Predy, R., and Malhotra, S.K., 1989, Reactive astrocytes in lesioned rat spinal cord: Effect of neural transplants, Brain Res. Bull 22: 81.PubMedCrossRefGoogle Scholar
  50. Quax, W.J., Egberts, W.V., Hendricks, W., Quax-Jeuken, Y.E.F.M., and Bloemendal, H., 1983, The structure of the vimentin gene, Cell 35: 215.PubMedCrossRefGoogle Scholar
  51. Quinlan, R.A., and Franke, W.W., 1983, Molecular interactions in intermediate sized filaments revealed by chemical cross-linking heteropolymers of vimentin and glial filament protein in cultured human glioma cells, Eur. J. Biochem. 132: 477.PubMedCrossRefGoogle Scholar
  52. Rataboul, R., Biguet, N.F., Vernier, P., De Vetry, F., Boularand, S., and Privat, A., 1988, Identification of a human glial fibrillary acidic protein cDNA: A tool for the molecular analysis of reactive gliosis in the mammalian central nervous system, J. Neurosci. Res. 20: 165.PubMedCrossRefGoogle Scholar
  53. Rataboul, R., Vernier, P., Biguet, N.F., Mallet, J., Pulat, P., and Privat, A., 1989, Modulation of GFAP mRNA levels following toxic lesions in the basal ganglia of the rat brain, Brain Res. Bull. 22: 155.PubMedCrossRefGoogle Scholar
  54. Reier, P.J., Eng, L.F., and Jakeman, L., 1989, Reactive astrocytes and axonal outgrowth in the injured CNS: Is gliosis really an impediment to regeneration?, in: “Neural Regeneration and Transplantation”, F.J. Seil, ed., Alan R. Liss Inc., New York.Google Scholar
  55. Riol, H., Fages, C., and Tardy, M., 1992, Transcriptional regulation of glial fibrillary acidic protein (GFAP)-mRNA expression during postnatal development of mouse brain, J. Neurosci. Res. 32: 79.PubMedCrossRefGoogle Scholar
  56. Schiffer, D., Giordana, M.T., Migheli, A., Giaccone, G., Pezzotta, A., and Mauro, A., 1986, Glial fibrillary acidic protein and vimentin in the experimental glial reaction of the rat brain, Brain Res. 374: 110.PubMedCrossRefGoogle Scholar
  57. Schnitzer, J., Franke, W.W., and Schachner, M., 1981, Immunocytochemical demonstration of vimentin in astrocytes and ependymal cells of the developing and adult mouse nervous system, J. Cell BioL 90: 435.PubMedCrossRefGoogle Scholar
  58. Selkoe, D.J., Salazar, F.J., Abraham, C., and Kosik, K.S., 1982, Huntington’s disease: Changes in striata] proteins reflect astrocytic gliosis, Brain Res. 245: 117.PubMedCrossRefGoogle Scholar
  59. Shafit-Zagardo, P., Kume-Iwaki, A., and Goldman, J.E., 1988, Astrocytes regulate GFAP mRNA levels by cyclic AMP and protein kinase C-dependent mechanisms, Glia 1: 346.PubMedCrossRefGoogle Scholar
  60. Sharp, G., Osborn, M., and Weber, K., 1982, Occurrence of two different intermediate filamentGoogle Scholar
  61. proteins in the same filament in situ within a human glioma cell line, Exp. Cell Res. 141: 385.Google Scholar
  62. Singh, D.N., and Mathew, T.C., 1989, Immunocytochemical studies of astrocytes following injury to the cerebral cortex of the rat, Acta. Anat 134: 156.PubMedCrossRefGoogle Scholar
  63. Smith, M.E., Somera, F.P., and Eng, L.F., 1983, Immunocytochemical staining for glial fibrillary acidic protein and the metabolism of cytoskeletal proteins in experimental autoimmune encephalomyelitis, Brain Res. 264: 241.PubMedCrossRefGoogle Scholar
  64. Steinert, P.M., and Liem, R.K.H., 1990, Intermediate filament dynamics, Cell 60: 521.PubMedCrossRefGoogle Scholar
  65. Steinert, P.M., and Roop, D.R., 1988, Molecular and cellular biology of intermediate filaments, Ann. Rev. Biochem. 57: 593.PubMedCrossRefGoogle Scholar
  66. Steinert, P.M., Steven, A.C., and Roop, D.R., 1985, The molecular biology of intermediate filaments, Cell 42: 411.PubMedCrossRefGoogle Scholar
  67. Steward, O., Torre, E.R., Phillips, L.L., and Trimmer, P.A., 1990, The process of reinnervation in the dentate gyms of adult rats: time course of increases in mRNA for glial fibrillary acidic protein, J. Neurosci. 10: 2373.PubMedGoogle Scholar
  68. Takamiya, Y., Koshaka, S., Toya, S., Otani, M., and Tsukada, Y., 1988, Immunohistochemical studies on the proliferation of reactive astrocytes and the expression of cytoskeletal proteins following brain injury in rats, Brain Res. 466: 201.PubMedGoogle Scholar
  69. Tapscott, S.J., Bennett, G.S., Toyama, Y., Kleinbart, F., and Holtzer, H., 1981, Intermediate filament proteins in the developing chick spinal cord, Dell. Biol. 86: 40.CrossRefGoogle Scholar
  70. Tardy, M., Fages, C., LePrince, G., Rolland, B., and Nunez, J., 1990, Regulation of the glial fibrillary acidic protein (GFAP) and of its encoding mRNA in the developing brain and in cultured astrocytes, in: “Molecular Aspects of Development and Aging of the Nervous System”Google Scholar
  71. J. Lauder, A. Privat, E. Giacobini, P. Timaris and A. Vernadakis, eds., Plenum Press, New York.Google Scholar
  72. Tardy, M., Fages, C., mol, H., LePrince, G., Rataboul, P., Charriere-Bertrand, C., and Nunez, J., 1989, Developmental expression of the glial fibrillary acidic protein mRNA in the central nervous system and in cultured astrocytes, J. Neurochem. 52: 162.PubMedCrossRefGoogle Scholar
  73. Tetzlaff, W., Graeber, M.B., Bisby, M.A., and Kreutzberg, G.W., 1988, Increased glial fibrillary acidic protein synthesis in astrocytes during retrograde reaction of the facial nucleus, Glia 1: 90.PubMedCrossRefGoogle Scholar
  74. Wang, E., Cairncross, J.G., and Liem, R.K.H., 1984, Identification of glial filament protein and vimentin in the same intermediate filament system in human glioma cells, Proc. Nat. Acad. Sci. USA 81: 2102.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Monica M. Oblinger
    • 1
    • 2
  • Susanne A. Kost
    • 1
    • 2
  • Leelabai D. Singh
    • 1
    • 2
  1. 1.Department of Cell Biology and AnatomyUniversity of Health SciencesUSA
  2. 2.The Chicago Medical SchoolNorth ChicagoUSA

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