Summary
This report describes a new inherited disorder of myelination in the rat, namedtaiep, in which failure of normal myelination of the CNS and subsequent demyelinatiori result in a progressive neurological disturbance. At two months of age, myelin is present throughout the spinal cord, but is immature in the fasciculus gracilis and corticospinal tracts despite the presence of abundant oligodendrocytes. By 12 months, myelin has largely been lost in these spinal cord tracts and also in more rostral parts of the CNS, such as the cerebellum and optic nerves. Other funiculi of the spinal cord show a more diffuse lack of myelin. Oligodendrocytes develop a unique cellular abnormality, most obviously in older rats, which is characterized by the accumulation of microtubules throughout their cytoplasm. As the mutant rats age, there is a continued protracted breakdown of myelin throughout the CNS, with evidence suggesting either persistent hypomyelination or attempts at remyelination of affected axons. It is proposed that the microtubular defect in oligodendrocytes results in a disruption of the normal myelination process in certain areas of the CNS of this mutant, and eventually leads to failure of maintenance of the myelin sheath.
Similar content being viewed by others
References
Baas, P. W., Slaughter, T., Brown, A. &Black, M. M. (1991a) Microtubule dynamics in axons and dendrites.Journal of Neuroscience Research 30, 134–53.
Baas, P. W., Pienkowski, T. P., &Kosik, K. S. (1991b) Processes induced by tau expression in Sf9 cells have an axon-like microtubule organization.Journal of Cell Biology 115, 1333–44.
Barron, K. D. (1987) Abnormalities of central axons in a dysmyelinative rat mutant.Experimental and Molecular Pathology 47, 125–42.
Baumann, N. (1980) Neurological mutations affecting myelination. InProceedings, Inserm Symposium No. 14. Amsterdam: Elsevier.
Brown, P. A. &Berlin, R. D. (1988) Factors that determine the spacing between microtubules: Their possible role in cytoarchitecture. InIntrinsic Determinants of Neuronal Form and Function (edited byLasek, R. J. &Black, M.) pp. 307–21. New York: A. R. Liss.
Bulinski, J. C. &Gundersen, G. G. (1991) Stabilization and post-translational modification of microtubules during cellular morphogenesis.Bioessays 13, 285–93.
Cooper, B. J., Duncan, I. D., Cummings, J. &Delahunta, A. (1984) Defective Schwann cell function in canine inherited hypertrophic neuropathy.Acta Neuropathologica 53, 51–6.
De Leon, M., Welcher, A. A., Suter, U. &Shooter, E. M. (1991) Identification of transcriptionally regulated genes after sciatic nerve injury.Journal of Neuroscience Research 29, 437–48.
Dentinger, M. P., Barron, K. D. &Csiza, C. (1985) Glial and axonal development in optic nerve of myelin deficient rat mutant.Brain Research 344, 255–66.
Duncan, I. D. (1990) Dissection of the phenotype and genotype of the X-linked myelin mutants.Annals of the New York Academy of Sciences 605, 110–21.
Duncan, I. D., Holmgren, B., Urba-Holmgren, R. &Riboni, L. (1989) Hypomyelination in a new neurological rat mutant.Society for Neuroscience Abstracts 15, 351.
Duncan, I. D., Skoff, R. P., &Colman, D. R., (eds). (1990a)Myelination and dysmyelination. Annals of the New York Academy of Sciences 605. New York: New York Academy of Sciences.
Dustin, P. (1984)Microtubules New York: Springer Verlag.
Dyer, C. A. &Benjamins, J. A. (1989) Organization of oligodendroglial membrane sheets. I. Association of myelin basic protein and 2′, 3′-cyclic nucleotide 3′-phosphohydrolase with cytoskeleton.Journal of Neuroscience Research 24, 210–11.
Fanarraga, M. L., Griffiths, I. R., McCulloch, M. C., Barrie, J. A., Kennedy, P. G. E. &Brophy, P. J. (1992) Rumpshaker: an X-linked mutation causing hypomyelination: developmental differences in myelination and glial cells between the optic nerve and spinal cord.Glia 5, 161–70.
Fischer, I., Konola, J. &Cochary, E. (1990) Microtubules associated with protein (map1b) is present in cultured oligodendrocytes and co-localizes with tubulin.Journal of Neuroscience Research 27, 112–24.
Freidrich, V. L. (1975) Hyperplasia of oligodendrocytes in quaking mice.Anatomy and Embryology 147, 259–71.
Garner, C., Garner, A., Huber, G. &Kozak, C., (1990) Molecular cloning of microtubule-associated protein 1 (mapla) and microtubule-associated protein 5 (maplb): identification of distinct genes and their differential expression in developing brain.Journal of Neurochemistry 55, 146–54.
Griffiths, I. R., Duncan, I. D. &McCulloch, M. (1981) Shaking pups: a disorder of central myelination in the spaniel dog. II. Ultrastructural observations on the white matter of the cervical spinal cord.Journal of Neurocytology 10, 847–58.
Griffiths, I. R., Scott, I., McCulloch, M. C., Barrie, J. A., McPhilemy, K. &Cattanach, B. M. (1990) Rumpshaker Mouse: a new X-linked mutation affecting myelination: Evidence for a defect in PLP expression.Journal of Neurocytology 19, 273–83.
Hedgecock, E. M., Culotti, J. G., Thomson, J. N. &Perkins, L. A. (1985) Axonal guidance mutants ofCaenorhabditis elegans identified by filling sensory neurons with fluorescein dyes.Developmental Biology 11, 158–70.
Heidemann, S. R., Landers, J. M. &Hamborg, M. A. (1981) Polarity orientation of axonal microtubules.Journal of Cell Biology 91, 661–5.
Hirano, A. (1978) A possible mechanism of demyelination in the Syrian hamster with hindleg paralysis.Laboratory Investigation 38, 115–21.
Hogan, E. L. &Greenfield, S. (1984) Animal models of genetic disorders of myelin. InMyelin 2nd ed. (edited byMorell, P.) pp. 489–534. New York: Plenum Press.
Holmgren, B., Urba-Holmgren, R., Riboni, L. &Vegasaenzdemiera, E. C. (1989) Sprague-Dawley rat mutant with tremor, ataxia, tonic immobility episodes, epilepsy and paralysis.Laboratory Animal Science 39, 226–8.
Hudson, L. D. &Nadon, N. L. (1992) Amino acid substitutions in proteolipid protein that cause dysmyelination. InMyelin: Biology and Chemistry 21 (edited byMartenson, R. E.) 677–702. Boca Raton; CRC Press.
Jackson, K. F. &Duncan, I. D. (1988) Cell kinetics and cell death in the optic nerve of the myelin deficient rat.Journal of Neurocytology 17, 657–70.
Katsuki, M., Sato, M., Kimura, M., Yokoyama, N., Kobayashi, K. &Namura, T. (1988) Conversion of normal behavior to shiverer by myelin basic protein antisense cDNA in transgenic mice.Science 241, 593–5.
Lemke, G. (1988) Unwrapping the genes of myelin.Neuron 1, 535–43.
Masurovsky, E. B., Peterson, E. R., Crain, S. M. &Horwitz, S. B. (1982) Taxol-induced microtubule formations in fibroblasts of fetal mouse dorsal root ganglionspinal cord cultures.Biology of the Cell 46, 213–16.
Masurovsky, E. B., Peterson, E. R., Crain, S. M. &Horwitz, S. B. (1983) Morphological alterations in dorsal root ganglion neurons and supporting cells of organotypic mouse spinal cord-ganglion cultures exposed to taxol.Neuroscience 10, 491–509.
Moller, J. R., Carmody, B. J., Durr, P. G., Holmgren, B., Urba-Holmgren, R., Brignolo-Holmes, L., Duncan, I. D. &Quarles, R. H. (1992) Biochemical analysis of myelin proteins in a new neurological rat mutant.Transactions of the American Society for Neurochemistry 23, 198.
Omlin, F. X. &Webster, H. Def. (1982) Immunocytochemical localization of basic protein in major dense line regions of central and peripheral myelin.Journal of Cell Biology 95, 242–8.
Pereyra, P. M., Horvath, E. &Braun, P. E. (1988) Triton X-100 extractions of central nervous system myelin indicate a possible role for the minor myelin proteins in the stability of lamellae.Neurochemical Research 13, 583–95.
Price, R. L., Lasek, R. J. &Katz, M. J. (1991) Microtubules have special physical associations with smooth endoplasmic reticula and mitochondria in axons.Brain Research 540, 209–16.
Raine, C. S. (1977) Schwann cell responses during recurrent demyelination and their relevance to onion-bulb formation.Neuropathology and Applied Neurobiology 2297, 453–70.
Readhead, C., Popko, B., Takahaski, N., Shire, H. D., Saavedra, R. A., Sedman, R. L. &Hood, L. E. (1987) Expression of a myelin basic protein gene in transgenic shiverer mice: Correction of the dysmyelinating phenotype.Cell 48, 703–12.
Remahl, S. &Hildebrand, C. (1990) Relation Between Axons and oligodendroglial cells during initial myelination. I. The glial unit.Journal of Neurocytology 19, 313–28.
Riederer, B., Cohen, R. &Matus, A. (1986) MAP5 A Novel Brain microtubule-associated protein under strong developmental regulation.Journal of Neurocytology 15, 763–75.
Roach, A., Boylan, K., Horvath, S., Prusiner, S. B. &Hood, L. E. (1983) Characterization of cloned cDNA representing rat myelin basic protein: Absence of expression in brain of shiverer mutant mice.Cell 34, 799–806.
Rosenfeld, J. &Freidrich, V. L. Jr. (1983) Axonal Swelling injimpy mice: does lack of myelin cause neuronal abnormalities?Neuroscience 10, 959–66.
Röytta, M. &Raine, C. S. (1985) Taxol-induced neuropathy: further ultrastructural studies of nerve fibre changesin situ.Journal of Neurocytology 14, 157–75.
Röytta, M., Horwitz, S. B. &Raine, C. S. (1984) Taxolinduced neuropathy: short term effects of local injection.Journal of Neurocytology 13, 685–701.
Safaei, R. &Fischer, I. (1989) Cloning of a cDN A encoding MAP1B in rat brain: regulation of mRNA levels during development.Journal of Neurochemistry 52, 1871–9.
Schoenfeld, T. A., McKerrader, L., Obar, R. &Vallee, R. B. (1989) Map 1A and map 1B are structurally related microtubule associated proteins with distinct developmental patterns in the CNS.Journal of Neuroscience 9, 1712–30.
Schwab, M. E. &Schnell, L. (1989) Region-specific appearance of myelin constituents in the developing rat spinal cord.Journal of Neurocytology 18, 161–9.
Shen, X-Y., Billings-Gagliardi, S., Sedman, R. L. &Wolf, M. K. (1985) Myelin deficient (shi-mld) mutant allele: Morphological comparison with shiverer (shi) allele on a B6C3 mouse stock.Brain Research 360, 235–47.
Skoff, R. P. &Knapp, P. E. (1992) Phenotypic expression of X-linked genetic defects affecting myelination. InMyelin: Biology and Chemistry 20 (edited byMartenson, R. E.) 653–76. Boca Raton: CRC Press.
Sutcliffe, J. G. (1988) The genes for myelin revisited.Trends in Genetics 4, 211–13.
Suter, U., Welcher, A. A., Özcelik, Snipes, G. J., Kosaras, B., Francke, U., Billings-Gagliardi, S., Sidman, R. L. &Shooter, E. M. (1992) Trembler mouse carries a point mutation in a myelin gene.Nature 356, 241–4.
Welcher, A. A., Suter, U., De Leon, M., Snipes, G. J. &Shooter, E. M. (1991) A myelin protein is encoded by the homologue of a growth arrest-specific gene.Proceedings of the National Academy of Sciences (USA) 88, 7195–9.
Wilson, R. &Brophy, P. J. (1989) Role for the oligodendrocyte cytoskeleton in myelination.Journal of Neuroscience Research 22, 439–48.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Duncan, I.D., Lunn, K.F., Holmgren, B. et al. The taiep rat: A myelin mutant with an associated oligodendrocyte microtubular defect. J Neurocytol 21, 870–884 (1992). https://doi.org/10.1007/BF01191684
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01191684