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Alterations in Gene Expression Associated with Primary Demyelination and Remyelination in the Peripheral Nervous System

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Abstract

Primary demyelination is an important component of a number of human diseases and toxic neuropathies. Animal models of primary demyelination are useful for isolating processes involved in myelin breakdown and remyelination because the complicating events associated with axonal degeneration and regeneration are not present. The tellurium neuropathy model has proven especially useful in this respect. Tellurium specifically blocks synthesis of cholesterol, a major component of PNS myelin. The resulting cholesterol deficit in myelin-producing Schwann cells rapidly leads to synchronous primary demyelination of the sciatic nerve, which is followed by rapid synchronous remyelination when tellurium exposure is discontinued. Known alterations in gene expression for myelin proteins and for other proteins involved in the sequence of events associated with demyelination and subsequent remyelination in the PNS are reviewed, and new data regarding gene expression changes during tellurium neuropathy are presented and discussed.

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REFERENCES

  1. Morell, P. 1994. Biochemical and molecular bases of myelinopathy. Pages 583–608, in Chang, L. W. (ed.), Principles of Neurotoxicology, Marcel Dekker, New York.

    Google Scholar 

  2. Quarles, R. H., Morell, P., and McFarlin, D. E. 1994. Diseases involving myelin. Pages 771–792, in Albers, R. W., Siegel, G. W., Molinoff, P. and Agranoff, B. (eds.), Basic Neurochemistry, (5th ed), Raven Press, New York.

    Google Scholar 

  3. Pleasure, D. E. 1993. Biochemistry of Neuropathy. Pages 761–770, in Albers, R. W., Siegel, G. W., Molinoff, P. and Agranoff, B. (eds.), Basic Neurochemistry, (5th ed), Raven Press, New York.

    Google Scholar 

  4. Morell, P., and Toews, A. D. 1997. Myelin and myelination as affected by toxicants. in Comprehensive Toxicology, in press.

  5. Towfighi, J. 1980. Hexachlorophene. Pages 440–455, in Spencer, P. S. and Schaumburg, H. H. (eds.), Experimental and Clinical Neurotoxicology, Williams and Wilkins, Baltimore.

    Google Scholar 

  6. Cammer, W. 1980. Toxic demyelination: Biochemical studies and hypothetical mechanisms. Pages 239–256, in Spencer, P. S. and Schaumburg, H. H. (eds.), Experimental and Clinical Neurotoxicology, Williams and Wilkins, Baltimore.

    Google Scholar 

  7. Watanabe, I. 1980. Organotins (Triethyltin). Pages 545–557, in Spencer, P. S. and Schaumburg, H. H. (eds.), Experimental and Clinical Neurotoxicology, Williams and Wilkins, Baltimore.

    Google Scholar 

  8. Lampert, P. W., and Garrett, R. S. 1971. Mechanism of demyelination in tellurium neuropathy. Electron microscopic observations. Lab. Invest. 25:380–388.

    Google Scholar 

  9. Duckett, S., Said, G., Streletz, L. G., White, R. G., and Galle, P. 1979. Tellurium-induced neuropathy: Correlative physiological, morphological and electron microprobe studies. Neuropathol. Appl. Neurobiol. 5:265–278.

    Google Scholar 

  10. Said, G., Duckett, S., and Sauron, B. 1981. Proliferation of Schwann cells in tellurium-induced demyelination in young rats. A radioautographic and teased nerve fiber study. Acta Neuropathol. (Berl) 53:173–179.

    Google Scholar 

  11. Takahashi, T. 1981. Experimental study on segmental demyelination in tellurium neuropathy. Hokkaido J. Med. Sci. 56:105–131.

    Google Scholar 

  12. Hammang, J. P., Duncan, I. D., and Gilmore, S. A. 1986. Degenerative changes in rat intraspinal Schwann cells following tellurium intoxication. Neuropathol. Appl. Neurobiol. 12:359–370.

    Google Scholar 

  13. Bouldin, T. W., Samsa, G., Earnhardt, T., and Krigman, M. R. 1988. Schwann-cell vulnerability to demyelination is associated with internodal length in tellurium neuropathy. J. Neuropathol. Exp. Neurol. 47:41–47.

    Google Scholar 

  14. Harry, G. J., Goodrum, J. F., Bouldin, T. W., Recio, M. W., Toews, A.D., and Morell, P. 1989. Tellurium-induced neuropathy: Metabolic alterations associated with demyelination and remyelination in rat sciatic nerve. J. Neurochem. 52:938–945.

    Google Scholar 

  15. Wagner-Recio, M., Toews, A. D., and Morell, P. 1991. Tellurium blocks cholesterol synthesis by inhibiting squalene metabolism: Preferential vulnerability to this metabolic block leads to peripheral nervous system demyelination. J. Neurochem. 57:1891–1901.

    Google Scholar 

  16. Toews, A. D., Goodrum, J. F., Lee, S. Y., Eckermann, C. E., and Morell, P. 1991. Tellurium-induced alterations in HMG-CoA reductase gene expression and enzyme activity: Differential effects in sciatic nerve and liver suggest tissue-specific regulation of cholesterol synthesis. J. Neurochem. 57:1902–1906.

    Google Scholar 

  17. Wagner, M., Toews, A. D., and Morell, P. 1995. Tellurite specifically affects squalene epoxidase: Investigations examining the mechanism of tellurium-induced neuropathy. J. Neurochem. 64: 2169–2176.

    Google Scholar 

  18. Rawlins, F. A., and Smith, M. E. 1971. Myelin synthesis in vitro: A comparative study of central and peripheral nervous tissue. J. Neurochem. 18:1861–1870.

    Google Scholar 

  19. Toews, A. D., Jurevics, H., Hostettler, J., Roe, E. B., and Morell, P. 1996. Tissue-specific coordinate regulation of enzymes of cholesterol biosynthesis: Sciatic nerve vs liver. J. Lipid Res. 37:2502–2509.

    Google Scholar 

  20. DeWille, J. W., and Horrocks, L. A. 1992. Synthesis and turnover of myelin phospholipids and cholesterol. Pages 213–234, in Martenson, R. E. (ed.), Myelin: Biology and Chemistry, CRC Press, Boca Raton, FL.

    Google Scholar 

  21. Morell, P., Quarles, R. H., and Norton, W. T. 1994. Myelin formation, structure, and biochemistry. Pages 117–143, in Albers, R. W., Siegel, G. W., Molinoff, P. and Agranoff, B. (eds.), Basic Neurochemistry, (5th ed), Raven Press, New York.

    Google Scholar 

  22. Toews, A. D., Lee, S. Y., Popko, B., and Morell, P. 1990. Tellurium-induced neuropathy: A model for reversible reductions in myelin protein gene expression. J. Neurosci. Res. 26:501–507.

    Google Scholar 

  23. Jessen, K. R., and Mirsky, R. 1991. Schwann cell precursors and their development. Glia 4:185–194.

    Google Scholar 

  24. Gould, R. M., Jessen, K. R., Mirsky, R., and Tennekoon, G. 1992. The cell of Schwann: An update. Pages 121–171, in Martenson, R. E. (ed.), Myelin: Biology and Chemistry, CRC Press, Boca Raton, FL.

    Google Scholar 

  25. Gupta, S. K., Poduslo, J. F., and Mezei, C. 1988. Temporal changes in P0 and MBP gene expression after crush-injury of the adult peripheral nerve. Brain Res. 464:133–141.

    Google Scholar 

  26. Gupta, S. K., Poduslo, J. F., Dunn, R., Roder, J., and Mezei, C. 1990. Myelin-associated glycoprotein gene expression in the presence and absence of Schwann cell-axonal contact. Dev. Neurosci. 12:22–30.

    Google Scholar 

  27. LeBlanc, A. C., and Poduslo, J. F. 1990. Axonal modulation of myelin gene expression in the peripheral nerve. J. Neurosci. Res. 26:317–326.

    Google Scholar 

  28. Trapp B. D., Hauer P., and Lemke G. 1988. Axonal regulation of myelin protein mRNA levels in actively myelinating Schwann cells. J. Neurosci. 8:3515–3521.

    Google Scholar 

  29. Goldstein, J. L., and Brown, M. S. 1990. Regulation of the mevalonate pathway. Nature 343:425–430.

    Google Scholar 

  30. Rudney, H., and Panini, S. R. 1993. Cholesterol biosynthesis. Curr Opin Lipidol. 4:230–237.

    Google Scholar 

  31. Russell, D. W. 1992. Cholesterol biosynthesis and metabolism. Cardiovasc. Drugs Therapy 6:103–110.

    Google Scholar 

  32. Goodrum, J. F. 1993. Cholesterol synthesis in regenerating peripheral nerve is not influenced by serum cholesterol levels. J. Neurochem. 60:1564–1566.

    Google Scholar 

  33. Jurevics, H. A., and Morell, P. 1994. Sources of cholesterol for kidney and nerve during development. J. Lipid Res. 35:112–120.

    Google Scholar 

  34. Toews, A. D., Eckermann, C. E., Lee, S. Y., and Morell, P. 1991. Primary demyelination induced by exposure to tellurium alters mRNA levels for nerve growth factor receptor, SCIP, 2′,3′-cyclic nucleotide 3′-phosphodiesterase, and myelin proteolipid protein in rat sciatic nerve. Mol. Brain Res. 11:321–325.

    Google Scholar 

  35. Welcher, A. A., Suter, U., De Leon, M., Snipes, G. J., and Shooter, E. M. 1991. A myelin protein is encoded by the homologue of a growth arrest-specific gene. Proc. Natl. Acad. Sci. USA 88:7195–7199.

    Google Scholar 

  36. Snipes, G. J., Suter, U., Welcher, A. A., and Shooter, E. M. 1992. Characterization of a novel peripheral nervous system myelin protein (PMP-22/SR13). J. Cell Biol. 117:225–238.

    Google Scholar 

  37. Trapp, B. D., Quarles, R. H., and Suzuki, K. 1984. Immunocytochemical studies of Quaking mice support a role for the myelinassociated glycoprotein in forming and maintaining the periaxonal space and periaxonal cytoplasmic collar in myelinating Schwann cells. J. Cell Biol. 99:595–606.

    Google Scholar 

  38. Owens, G. C., and Bunge, R. P. 1991. Schwann cells infected with a recombinant retrovirus expressing myelin-associated glycoprotein antisense RNA do not form myelin. Neuron 7:565–575.

    Google Scholar 

  39. Trapp, B. D. 1988. Distribution of the myelin-associated glycoprotein and P0 protein during myelin compaction in quaking mouse peripheral nerve. J. Cell Biol. 107:675–685.

    Google Scholar 

  40. Quarles, R. H., Hammer, J. A., and Trapp, B. D. 1990. The immunoglobulin gene superfamily and myelination. Pages 49–79, in Hashim, G. A. and Moscarello, M. (eds.), Dynamic Interactions of Myelin Proteins, Raven Press, New York.

    Google Scholar 

  41. Quarles, R. H., Colman, D. R., Salzer, J. L., and Trapp, B. D. 1992. Myelin-associated glycoprotein: Structure-function relationships and involvement in neurological diseases. Pages 413–448, in Martenson, R. E. (ed.), Myelin: Biology and Chemistry, CRC Press, Boca Raton, FL.

    Google Scholar 

  42. Mitchell, L. S., Griffiths, I. R., Morrison, S., Barrie, J. A., Kirkham, D., and McPhilmey, K. 1990. Expression of myelin protein gene transcripts by Schwann cells of regenerating nerve. J. Neurosci. 27:125–135.

    Google Scholar 

  43. De Angelis, D. A., and Braun, P. E. 1996. 2′,3′-cyclic nucleotide 3′-phosphodiesterase binds to actin-based cytoskeletal elements in an isoprenylation-independent manner. J. Neurochem. 67:943–951.

    Google Scholar 

  44. Braun, P. E., and Barchi, R. L. 1972. 2′,3′-Cyclic nucleotide 3′-phosphodiesterase in the nervous system. Electrophoretic properties and developmental studies. Brain Res. 40:437–444.

    Google Scholar 

  45. Matthieu, J.-M., Waehneldt, T. V., Webster, H.deF., Beny, M., and Fag, G. E. 1979. Distribution of PNS myelin proteins and membrane enzymes in fractions isolated by continuous gradient zonal centrifugation. Brain Res. 170:123–133.

    Google Scholar 

  46. Edwards, A. M., and Braun, P. E. 1988. Gene expression of the central and peripheral nervous system myelin membrane 2′,3′-cyclic nucleotide 3′-phosphodiesterase in development. Dev. Neurosci. 10:75–80.

    Google Scholar 

  47. Puckett, C., Hudson, L., Ono, K., Friedrich, V., Benecke, J., Dubois-Dalc, M., and Lazzarini, R. A. 1987. Myelin-specific proteolipid protein is expressed in myelination Schwann cells but is not incorporated into myelin sheaths. J. Neurosci. Res. 18:511–518.

    Google Scholar 

  48. Toews, A. D., Griffiths, I. R., Kyriakides, E., Goodrum, J. F., Eckermann, C. E., Morell, P., and Thomson, C. E. 1992. Primary demyelination induced by exposure to tellurium alters Schwann-cell gene expression: A model for intracellular targeting of NGF-receptor. J. Neurosci. 12:3676–3687.

    Google Scholar 

  49. Hudson, L. D. 1990. Molecular biology of myelin proteins in the central and peripheral nervous systems. Sem. Neurosci. 2:483–496.

    Google Scholar 

  50. Hudson, L. D., Ko, N., and Kim, J. G. 1995. Control of myelin gene expression in glial development: Basic principles and clinical relevance. Pages 101–121, in Richardson, W. D. and Jessen, K. R. (eds.), Glial Cell Development, Bios Scientific Publishing, London.

    Google Scholar 

  51. Monuki, E. S., Weinmaster, G., Kuhn, R., and Lemke, G. 1989. SCIP: A glial POU domain gene regulated by cyclic AMP. Neuron 3:783–793.

    Google Scholar 

  52. Stoll, G., Li, C. Y., Trapp, B. D., and Griffin, J. W. 1993. Expression of NGF-receptors during immune-mediated and lysolecithin-induced demyelination of the peripheral nervous system. J. Neurocytol. 22:1022–1029.

    Google Scholar 

  53. Conti, G., Baron, P. L., Scarpini, E., Vedeler, C., Rostami, A., Pleasure, D., and Scarlato, G. 1995. Low-affinity nerve growth factor receptor expression in sciatic nerve during P2-peptide induced experimental allergic neuritis. Neurosci. Lett. 199:135–138.

    Google Scholar 

  54. Heumann, R., Lindholm, D., Bandtlow, C., Meyer M., Radeke, M. J., Misko, T. P., Shooter, E., and Thoenen, H. 1987. Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc. Natl. Acad. Sci. USA 84:8735–9739.

    Google Scholar 

  55. Lemke, G., and Chao, M. 1988. Axons regulate Schwann cell expression of the major myelin and NGF receptor genes. Development 102:499–504.

    Google Scholar 

  56. Taniuchi, M., Clark, H. B., and Johnson, E. M., Jr. 1986. Induction of nerve growth factor receptor in Schwann cells after axotomy. Proc. Natl. Acad. Sci. USA 83:4094–4098.

    Google Scholar 

  57. Taniuchi, M., Clark, H. B., Schweitzer, J. B., and Johnson, E. M. 1988. Expression of nerve growth factor receptors by Schwann cells of axotomoized peripheral nerves: ultrastructural location, suppression by axonal contact, and binding properties. J. Neurosci. 8:664–681.

    Google Scholar 

  58. Monuki, E. S., Kuhn, R., Weinmaster, G., Trapp, B. D., and Lemke, G. 1990. Expression and activity of the POU transcription factor SCIP. Science 249:1300–1303.

    Google Scholar 

  59. Weinstein, D. E., Burrola, P. G., and Lemke, G. 1995. Premature Schwann cell differentiation and hypermyelination in mice expressing a targeted antagonist of the POU transcription factor SCIP. Mol. Cell. Neurosci. 6:212–229.

    Google Scholar 

  60. Scherer, S. S., Wang, D., Kuhn, R., Lemke, G., Wrabetz, L., and Kamholz, J. 1994. Axons regulate Schwann cell expression of the POU transcription factor SCIP. J. Neurosci. 14:1930–1942.

    Google Scholar 

  61. Ip, N. P., and Yancopoulos, G. D. 1996. The neurotrophins and CNTF: Two families of collaborative neurotrophic factors. Ann. Rev. Neurosci. 19:491–515.

    Google Scholar 

  62. Ip, N. P., and Yancopoulos, G. D. 1992. Ciliary neurotrophic factor and its receptor complex. Prog. Growth Factor Res. 4:139–155.

    Google Scholar 

  63. Friedman, B., Scherer, S. S., Rudge, J. S., Helgren, M., Morrisey, D., McClain, J., Wang, D., Wiegand, S. J., Furth, M. E., Lindsay, R. M., and Ip, N. Y. 1992. Regulation of ciliary neurotrophic factor expression in myelin-related Schwann cells in vivo. Neuron 9:295–305.

    Google Scholar 

  64. Rabinovsky, E. D., Smith, G. M., Browder, D. P., Shine, H. D., and McManaman, J. L. 1992. Peripheral nerve injury down-regulates CNTF expression in adult rat sciatic nerves. J. Neurosci. Res. 31:188–192.

    Google Scholar 

  65. Sendtner, M. K., Stöckli, K. A., and Thoenen, H. 1992. Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration. J. Cell Biol. 118:139–148.

    Google Scholar 

  66. Smith, G. M., Rabinovsky, E. D., McManaman, J. L., and Shine, H. D. 1993. Temporal and spatial expression of ciliary neurotrophic factor after peripheral nerve injury. Exp. Neurol. 121:239–247.

    Google Scholar 

  67. Perry, V. H., and Brown, M. C. 1992. Macrophages and nerve regeneration. Curr. Opin. Neurobiol. 2:679–682.

    Google Scholar 

  68. Perry, V. H., and Brown, M. C. 1992. Role of macrophages in peripheral nerve degeneration and repair. BioEssays 14:401–406.

    Google Scholar 

  69. Friede, R. L., and Brüch, W. 1993. Macrophage functional properties during myelin degradation. Adv. Neurol. 59:327–336.

    Google Scholar 

  70. Griffin, J. W., George, R., and Ho, T. 1993. Macrophage systems in peripheral nerves. A review. J. Neuropath. Exp. Neurol. 52: 553–560.

    Google Scholar 

  71. Goodrum, J. F., Earnhardt, T., Goines, N., and Bouldin, T. W. 1994. Fate of myelin lipids during degeneration and regeneration of peripheral nerve: An autoradiographic study. J. Neurosci. 14: 357–367.

    Google Scholar 

  72. Goodrum, J. F., Weaver, J. E., Goines, N. D., and Bouldin, T. W. 1995. Fatty acids from degenerating myelin lipids are conserved and reutilized for myelin synthesis during regeneration in peripheral nerve. J. Neurochem. 65:1752–1759.

    Google Scholar 

  73. Venezie, R. D., Toews, A. D., and Morell, P. 1995. Macrophage recruitment in different models of nerve injury: Lysozyme as a marker for active phagocytosis. J. Neurosci. Res. 40:99–107.

    Google Scholar 

  74. Hirschberg, D. L., Yoles, E., Belkin, M., and Schwartz, M. 1994. Inflammation after axonal injury has conflicting consequences for recovery of function: Rescue of spared axons is impaired but regeneration is supported. J. Neuroimmunol. 50:9–16.

    Google Scholar 

  75. Lotan, M., and Schwartz, M. 1994. Cross talk between ithe immune system and the nervous system in response to injury: Implications for regeneration. FASEB J. 8:1026–1033.

    Google Scholar 

  76. Gibbs, J. B. 1991. Ras C-terminal processing enzymes—New drug targets? Cell 65:1–4.

    Google Scholar 

  77. Glomset, J. A., Gelb, M. H., and Farnsworth C. C. 1992. Geranylgeranylated proteins. Biochem. Soc. Trans. 20:479–484.

    Google Scholar 

  78. Bouldin, T. W., Earnhardt, T., and Goines, N. D. 1991. Restoration of blood-nerve barrier in neuropathy is associated with axonal regeneration and remyelination. J. Neuropathol. Exp. Neurol. 50: 719–728.

    Google Scholar 

  79. Chirgwin, J. M., Przybyla, A. E., MacDonald, R. J., and Rutter, W. J. 1979. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18:5294–5299.

    Google Scholar 

  80. Pauley, R. J., Parks, W. P., and Popko, B. J. 1984. Expression and demethylation of germinally-transmitted BALB/c mouse mammary tumor virus DNA in Abelson MuLV B-lymphoid cell lines. Virus Res. 1:381–400.

    Google Scholar 

  81. Jansen, R., and Ledley, F. D. 1989. Production of high specific activity DNA probes using the polymerase chain reaction. Gene. Anal. Techn. 6:79–83.

    Google Scholar 

  82. Bednarczuk, T. A., Wiggins, R. C., and Konat, G. W. 1991. Generation of high efficiency, single-stranded DNA hybridization probes by PCR. Bio Techniques. 10:478.

    Google Scholar 

  83. Lemke, G., and Axel, R. 1985. Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell 40:501–508.

    Google Scholar 

  84. Day, R., Gebhard, R. L., Schwartz, H. L., Strait, K. A., Duane, W. C., Stone, B. G., and Oppenheimer, J. H. 1989. Time course of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase and messenger ribonucleic acid, biliary lipid secretion, and hepatic cholesterol content in methimazole-treated hypothyroid and hypophysectomized rats after triiodothryonine administration: Possible linkage of cholesterol synthesis to biliary secretion. Endocrinology 125:459–468.

    Google Scholar 

  85. Stahl, N., Jurevics, H., Morell, P., Suzuki, K., and Popko, B. 1994. Isolation, characterization, and expression of cDNA clones that encode UDP-galactose: ceramide galactosyltransferase. J. Neurosci. Res. 38:234–242.

    Google Scholar 

  86. Maniatis, T., Fritsch, E. F., and Sambrook, J. 1982. Molecular Cloning, pp. 122–123. Cold Spring Harbor, New York.

    Google Scholar 

  87. Hadjiolov, A. A., Georgiev, O. I., Nosikov, V. V., and Yavachev, L. P. 1984. Primary and secondary structure of rat 28 S ribosomal RNA. Nuc. Acids Res. 12:3677–3693.

    Google Scholar 

  88. Lai, C., Brow, M. A., Nave, K.-A., Noronha, A. B., Quarles, R. H., Bloom, F. E., Milner, R. J., and Sutcliffe, J. G. 1987. Two forms of 1B236/myelin-associated glycoprotein, a cell adhesion molecule for postnatal neural development, are produced by alternative splicing. Proc. Natl. Acad. Sci. USA 84:4337–4341.

    Google Scholar 

  89. Feinberg, A. P., and Vogelstein, B. 1983. A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem. 132:6–13.

    Google Scholar 

  90. Raedeke, M. J., Misko, T. P., Hsu, C., Herzenberg, L. A., and Shooter, E. M. 1987. Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature 325:593–597.

    Google Scholar 

  91. Stöckli, K. A., Lottspeich, F., Sendtner, M., Masiakowski, P., Carroll, P., Götz, R., Lindholm, D., and Thoenen, H. 1989. Molecular cloning, expression and regional distribution of rat ciliary neurotrophic factor. Nature 342:920–923.

    Google Scholar 

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Toews, A.D., Hostettler, J., Barrett, C. et al. Alterations in Gene Expression Associated with Primary Demyelination and Remyelination in the Peripheral Nervous System. Neurochem Res 22, 1271–1280 (1997). https://doi.org/10.1023/A:1021941215310

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