Abstract
The roles that the myelin galactolipids galactocerebroside (GalC) and sulfatide play in cellular differentiation, myelin formation and maintenance have been investigated for nearly 3 decades. During that time the primary approach has been to perturb lipid activity using antibodies and chemical agents in artificial systems. Recently, the isolation of the gene that encodes UDP-galactose:ceramide galactosyltransferase (CGT), the enzyme that catalyzes an essential step in the synthetic pathway of GalC and sulfatide, has enabled the generation of mice that lack myelin galactolipids. These mice display a severe tremor, hindlimb paralysis and electrophysiological defects. In addition, the CGT null mutants exhibit: 1) impaired oligodendrocyte differentiation, 2) myelin sheaths that are thin, incompletely compacted and unstable, and 3) structural abnormalities in the nodal and paranodal regions including disrupted axo-glial junctions. Collectively, these findings suggest that GalC and sulfatide are essential in myelin formation and maintenance, possibly by mediating intra- and intercellular interactions.
Similar content being viewed by others
References
Bansal, R., Gard A. L. & Feiffer, S. E. (1988) Stimulation of oligodendrocyte differentiation in culture by growth in the presence of a monoclonal antibody to sulfated glycolipid. Journal of Neuroscience Research 21, 260–267.
Bansal, R. & fieffer, S. E. (1989) Reversible inhibition of oligodendrocyte progenitor differentiation by a monoclonal antibody against surface galactolipids. Proceedings of the National Academy of Sciences U.S.A. 86, 6181–6185.
Bansal, R. & feiffer, E. S. (1994) Regulation of gene expression in mature oligodendrocytes by the specialized myelin-like membrane environment: antibody perturbation in culture with the monoclonal antibody R-mAb. Glia 12, 173–179.
Bansal, R., Warrington, A. E., Gard, A. L., Ranscht, B. & feiffer, S. E. (1989) Multiple and novel specificities of monoclonal antibodies 01, 04, and R-mAb used in the analysis of oligodendrocyte development. Journal of Neuroscience Research 24, 548–557.
Barbour, S., Edidin, M., Felding-Habermann, B., Taylor-Norton, J., Radin, N. S. & Fenderson, B. A. (1992) Glycolipid depletion using a ceramide analogue (PMDP) alters growth, adhesion, and membrane lipid organization in human A431 cells. Journal of Cellular Physiology 150, 610–619.
Benjamins, J. A. & Dyer, C. A. (1990) Glycolipids and transmembrane signaling in oligodendroglia. Annals of the New York Academy of Science 605, 90–100.
Bosio, A., Binczek, E. & Stoffel, W. (1996) Functional breakdown of the lipid bilayer of the myelin membrane in central and peripheral nervous system by disrupted galactocerebroside synthesis. Proceedings of the National Academy of Sciences USA 93, 13280–13285.
Bosio, A., Bussow, H., Adam, J. & Stoffel, W. (1998) Galactosphingolipids and axono-glial interaction in myelin of the central nervous system. Cell and Tissue Research 292, 199–210.
Cestaro, B., Cervato, G., Marchesini, S., Viani, P., Pistolesi, E. & Oliva, C. (1983) Electron spin resonance studies on the dynamics of phosphatidylcholine-sulfatide model membranes. Chemistry and Physics of Lipids 33, 251–262.
Coetzee, T., Fujita, N., Dupree, J., Shi, R., Blight, A., Suzuki, K., Suzuki, K. & Popko, B. (1996) Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional stability. Cell 86, 209–219.
Coetzee, T., Dupree, J. L. & Popko, B. (1998a) Demyelination and altered expression of myelin-associated glycoprotein isoforms in the central nervous system of galactolipid-deficient mice. Journal of Neuroscience Research 54, 613–622.
Coetzee, T., Suzuki, K. & Popko, B. (1998b) New perspectives on the function of myelin galactolipids. Trends in Neuroscience 21, 126–130.
Coetzee, T., Suzuki, K., Nave, K.-A. & Popko, B. (1999) Myelination in the absence of galactolipids and proteolipid proteins. Molecular and Cellular Neuroscience 14, 41–51.
Duncan, I. D., Hammang, J. P. & Trapp, B. D. (1987) Abnormal compact myelin in the myelin-deficient rat: absence of proteolipid protein correlates with a defect in the intermediate line. Proceedings of the National Academy of Sciences USA 84, 6287–6291.
Dugandzija-Novakovic, S., Koszowski, A. G., Levinson, S. R. & Shrager, P. (1995) Clustering of Na+ channels and node of Ranvier formation in remyelinating axons. Journal of Neuroscience 15(1), 492–503.
Dupree, J. L., Suzuki, K. & Popko, B. (1998a) Galactolipids in the formation and function of the myelin sheath. Microscopy Research and Technique 41, 431–440.
Dupree, J. L., Coetzee, T., Blight, A., Suzuki, K. & Popko, B. (1998b) Myelin galactolipids are essential for proper node of Ranvier formation in the CNS. Journal of Neuroscience 18, 1642–1649.
Dupree, J. L., Coetzee, T., Suzuki, K. & Popko, B. (1998c) Myelin abnormalities in mice deficient in galactocerebroside and sulfatide. Journal of Neurocytology 27, 649–659.
Dyer, C. A. & Benjamins, J. A. (1988) Antibody to galactocerebroside alters organization of oligodendroglial membrane sheets in culture. Journal of Neuroscience 8, 4307–4318.
Gard, A. L. & Pfeiffer, S. E. (1989) Oligodendrocyte progenitors isolated directly from developing telencephalon at a specific phenotypic stage: myelinogenic potential in a defined environment. Development 106, 119–132.
Gould, R. M., Byrd, A. L. & Barbarese, E. (1995) The number of Schmidt-Lanterman incisures is more abundant in shiverer PNS myelin sheaths. Journal of Neurocytology 24, 85–98.
Hakomori, S-I. (1990) Bifunctional role of glycosphingolipids. Journal of Biological Chemistry 265, 18713–18716.
Hildebrand, D., Remahl, S., Persson, H. & Bjartmar, C. (1993) Myelinated nerve fibers in the CNS. Progress in Neurobiology 40, 319–384.
Kan, C. C. & Kolesnick, R. N. (1992) A synthetic ceramide analog, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol selectively inhibits adherence during macrophage differentiation of human leukemia cells. Journal of Biological Chemistry 267(14), 9663–9667.
Kennedy, P. G., Lisak, R. P. & Raff, M. C. (1980) Cell type-specific markers for human glial and neuronal cells in culture. Laboratory Investigation 43(4), 342–351.
Klugmann, M., Schwab, M.H., Puhlhofer, A., Schneider, A., Zimmerman, F., Griffiths, I. R. & Nave, K.-A. (1997) Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18, 59–70.
Koynova, R. & Caffrey, M. (1995) Phases and phase transitions of the sphingolipids. Biochimica et Biophysica Acta 1255, 213–236.
Kramer, E., Koch, T., Niehaus, A. & Trotter, J. (1997) Oligodendrocytes direct glycosyl phosphatidylinositol-anchored proteins to the myelin sheath in glycosphingolipid-rich complexes. Journal of Biological Chemistry 272, 8937–8945.
Ledesma, M. D., Simons, K. & Dotti, C. G. (1998) Neuronal polarity: essential role of protein-complexes in axonal sorting. Proceedings of the National Academy of Sciences USA. 95, 3966–3971.
Less, M. & Brostoff, S. L. (1984) Protein of myelin. In Myelin, 2nd ed. (edited by Morell, P.), pp. 197–224. New York: Plenum Press.
Marcus, J. R., Dupree, J. L. & Popko, B. (submitted) Effects of myelin galactolipid elimination on oligodendrocyte development. Glia.
Morell, P. & Radin, N. S. (1969) Synthesis of cerebroside by brain from uridine diphosphate galactose and ceramide containing hydroxy fatty acid. Biochemistry 8, 506–512.
Norton, W. T. & Cammer, W. (1984) Isolation and characterization of myelin. In Myelin (edited byMorell, P.) pp. 147–196. New York: Plenum Press.
Owens, G. C. & Bunge, R. P. (1990) Schwann cells depleted of galactocerebroside express myelin-associated glycoprotein and initiate but do not continue the process of myelination. Glia 3, 118–124.
Peshva, P., Gloor, S., Schachner, M. & Probstmeir, R. (1997) Tenascin-R is an intrisic autocrine factor for oligodendrocyte differentiation and promotes cell adhesion by a sulfatide mediated mechanism. Journal of Neuroscience 17(12), 4642–4651.
Raff, M. C., Mirsky, R., Fields, K. L., Lisak, R. P., Dorfman, S. H., Silberberg, D. H., Gregson, N. A., Leibowitz, S. & Kennedy, M. C. (1978) Galactocerebroside is a specific cell-surface antigenic marker for oligodendrocytes in culture. Nature 274, 813–816.
Ranscht, B., Wood, P. M. & Bunge R. P. (1987) Inhibition of in vitro peripheral myelin formation by monoclonal anti-galactocerebroside. Journal of Neuroscience 7, 2936–2947.
Reynolds, R. & Wilkin, G. P. (1988) Development of macroglial cells in rat cerebellum. II. An in situ immunohistochemical study of oligodendroglial lineage from Myelin galactolipid function 279 precursor to mature myelinating cell. Development 102, 409–425.
Rosenbluth, J. (1966) Redundant myelin sheaths and other ultrastructural features of the toad cerebellum. Journal of Cell Biology 28(1), 73–93.
Rosenbluth, J., Liang, W.-L., Liu, Z., Guo, D. & Schiff, R. (1995) Paranodal structural abnormalities in rat CNS myelin developing in vivo in the presence of implanted 01 hybridoma cells. Journal of Neurocytology 24, 818–824.
Rosenbluth, J., Liang, W. L., Liu, Z., Guo, D. & Schiff, R. (1996a) Expanded CNS myelin sheaths formed in situ in the presence of an IgM antigalactocerebroside-producing hybridoma. Journal of Neuroscience 16(8), 2635–2641.
Rosenbluth, J., SToffel, W. & Schiff, R. (1996b) Myelin structure In proteolipid protein (PLP)-null mouse spinal cord. The Journal of Comparative Neurology 371, 336–344.
Saida, T., Saida, K. & Silberberg, D. H. (1979a) Demyelination produced by experimental allergic neuritis serum and antigalactocerebroside antiserum in CNS cultures. Acta Neuropathologica 48, 19–25.
Saida, K., Saida, T., Brown, M. J. & Silberberg, D. H. (1979b) In vivo demyelination induced by intraneural injection of anti-galactocerebroside serum a morphological study. American Journal of Pathology 95, 99–116.
Saito, M., Macala, L. J., Roth, G. A., Bornstein, M. B. & Yu, R. K. (1986) Effect of antiglycolipid antisera on the lipid composition of cultured mouse spinal cords. Experimental Neurology 92, 752–756.
Sergott, R. C., Brown, M. J. & Silberberg, D. H. (1986) Remyelination follows anti-body induced central nervous system demyelination. Annales of Neurology 20, 94–98.
Shevchenko, A., Keller, P., Scheiffele, P., Mann, M. & Simons, K. (1997) Identification of components of trans-Golgi network-derived transport vesicles and detergent-insoluble complexes by nanoelectrospray tandem spectrometry. Electrophoresis 18, 2591–2600.
Simons, K. & Ikonen, E. (1997) Functional rafts in cell membranes. Nature 387, 569–572.
Suzuki, K., Vanier, M. T., Coetzee, T. & Popko, B. (1999) Drastically abnormal gluco-and galactosylceramide composition does not affect ganglioside metabolism in the brain of mice deficient in galactosylceramide synthase. Neurochemical Research 24(4), 461–464.
Van Meer, G., Van genderen, I. L., Van't hof, W., Burger, K. N. J. & Van Dper Bijl, P. (1993) Lipid transport from the Golgi to the plasma membrane of epithelial cells. In Molecular Mechanisms of Membrane Traffic (edited by Morre, D. J., Howell, K. E. & Bergeron, J. J. M.), pp. 181–185, Berlin: Springer Verlag.
Vos, J. P., Lopes-cardozo, M. & Gadella, B. M. (1994) Metabolic and functional aspects of sulfogalactolipids. Biochimica et Biophysica Acta 1211, 125–149.
Yamaji, T., Miyake, Y., Kozutsumi, Y. & Kawasaki, T. (1997) Neutral glycosphingolipids induce cell-cell aggregation of a variety of hematopoietic cell lines. European Journal of Biochemistry 247, 21–29.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dupree, J.L., Popko, B. Genetic dissection of myelin galactolipid function. J Neurocytol 28, 271–279 (1999). https://doi.org/10.1023/A:1007049310758
Issue Date:
DOI: https://doi.org/10.1023/A:1007049310758