Myelination and support of axonal integrity by glia

Article metrics

Abstract

The myelination of axons by glial cells was the last major step in the evolution of cells in the vertebrate nervous system, and white-matter tracts are key to the architecture of the mammalian brain. Cell biology and mouse genetics have provided insight into axon–glia signalling and the molecular architecture of the myelin sheath. Glial cells that myelinate axons were found to have a dual role by also supporting the long-term integrity of those axons. This function may be independent of myelin itself. Myelin abnormalities cause a number of neurological diseases, and may also contribute to complex neuropsychiatric disorders.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Oligodendrocyte defects causing axonal degeneration in the central nervous system.
Figure 2: Oligodendrocyte defects may lead to cognitive impairment.

References

  1. 1

    Sherman, D. L. & Brophy, P. J. Mechanisms of axon ensheathment and myelin growth. Nature Rev. Neurosci. 6, 683–690 (2005).

  2. 2

    Jessen, K. R. & Mirsky, R. The origin and development of glial cells in peripheral nerves. Nature Rev. Neurosci. 6, 671–682 (2005).

  3. 3

    Simons, M. & Trotter, J. Wrapping it up: the cell biology of myelination. Curr. Opin. Neurobiol. 17, 533–540 (2007).

  4. 4

    Salzer, J. L., Brophy, P. J. & Peles, E. Molecular domains of myelinated axons in the peripheral nervous system. Glia 56, 1532–1540 (2008).

  5. 5

    Geren, B. B. & Raskind, J. Development of the fine structure of the myelin sheath in sciatic nerves of chick embryos. Proc. Natl Acad. Sci. USA 39, 880–884 (1953). This classic work demonstrated, using electron microscopy, that myelin is a glial-cell ensheathment of axons, rather than a specialization of axons.

  6. 6

    Bullock, T. H., Moore, J. K. & Fields, R. D. Evolution of myelin sheaths: both lamprey and hagfish lack myelin. Neurosci. Lett. 48, 145–148 (1984).

  7. 7

    Zalc, B., Goujet, D. & Colman, D. The origin of the myelination program in vertebrates. Curr. Biol. 18, R511–R512 (2008).

  8. 8

    Hartline, D. K. What is myelin? Neuron Glia Biol. 4, 153–163 (2008).

  9. 9

    Sowell, E. R. et al. Mapping cortical change across the human lifespan. Nature Neurosci. 6, 309–315 (2003).

  10. 10

    Griffin, J. W. & Thompson, W. J. Biology and pathology of nonmyelinating Schwann cells. Glia 56, 1518–1531 (2008).

  11. 11

    Chen, S. et al. Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Nature Neurosci. 6, 1186–1193 (2003). Although they were generated for a different purpose, the mutants reported in this study demonstrate that Remak cells are required for the integrity of unmyelinated C-fibre axons.

  12. 12

    Nave, K. A. & Trapp, B. D. Axon–glial signaling and the glial support of axon function. Annu. Rev. Neurosci. 31, 535–561 (2008).

  13. 13

    Taveggia, C. et al. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47, 681–694 (2005). The first paper to show that cultured sympathetic neurons, virally transduced to overexpress NRG1, instruct associated Schwann cells to myelinate thin axons de novo.

  14. 14

    Trotter, J., Karram, K. & Nishiyama, A. NG2 cells: Properties, progeny and origin. Brain Res. Rev. 63, 72–82 (2010).

  15. 15

    Bergles, D. E., Jabs, R. & Steinhauser, C. Neuron–glia synapses in the brain. Brain Res. Rev. 63, 130–137 (2010).

  16. 16

    Káradóttir, R., Hamilton, N. B., Bakiri, Y. & Attwell, D. Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter. Nature Neurosci. 11, 450–456 (2008). The only report so far that some precursor cells of myelin-forming oligodendrocytes can be triggered to generate action potentials.

  17. 17

    Nave, K.-A. & Salzer, J. L. Axonal regulation of myelination by neuregulin 1. Curr. Opin. Neurobiol. 16, 492–500 (2006).

  18. 18

    Griffiths, I. et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610–1613 (1998). The first paper to show that oligodendrocytes serve the vital function of preserving the integrity and survival of axons, independent of myelin formation.

  19. 19

    Edgar, J. M. et al. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J. Cell. Biol. 166, 121–131 (2004).

  20. 20

    Lappe-Siefke, C. et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nature Genet. 33, 366–374 (2003).

  21. 21

    Edgar, J. M. et al. Early ultrastructural defects of axons and axon–glia junctions in mice lacking expression of Cnp1 . Glia 57, 1815–1824 (2009).

  22. 22

    Yin, X. et al. Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J. Neurosci. 18, 1953–1962 (1998).

  23. 23

    Wang, S. S. et al. Functional trade-offs in white matter axonal scaling. J. Neurosci. 28, 4047–4056 (2008).

  24. 24

    Nave, K. A. Myelination and the trophic support of long axons. Nature Rev. Neurosci. 11, 275–283 (2010).

  25. 25

    de Waegh, S. M., Lee, V. M. & Brady, S. T. Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell 68, 451–463 (1992).

  26. 26

    Brady, S. T. et al. Formation of compact myelin is required for maturation of the axonal cytoskeleton. J. Neurosci. 19, 7278–7288 (1999).

  27. 27

    Quarles, R. H. Myelin-associated glycoprotein (MAG): past, present and beyond. J. Neurochem. 100, 1431–1448 (2007).

  28. 28

    Nguyen, T. et al. Axonal protective effects of the myelin-associated glycoprotein. J. Neurosci. 29, 630–637 (2009).

  29. 29

    Simon, C. M., Jablonka, S., Ruiz, R., Tabares, L. & Sendtner, M. Ciliary neurotrophic factor-induced sprouting preserves motor function in a mouse model of mild spinal muscular atrophy. Hum. Mol. Genet. 19, 973–986 (2010).

  30. 30

    Keswani, S. C. et al. A novel endogenous erythropoietin mediated pathway prevents axonal degeneration. Ann. Neurol. 56, 815–826 (2004).

  31. 31

    Riethmacher, D. et al. Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389, 725–730 (1997). A genetic study providing evidence that before myelination, Schwann cells are essential for the survival of neurons in dorsal-root ganglia.

  32. 32

    Klugmann, M. et al. Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18, 59–70 (1997).

  33. 33

    Rosenbluth, J., Nave, K. A., Mierzwa, A. & Schiff, R. Subtle myelin defects in PLP-null mice. Glia 54, 172–182 (2006).

  34. 34

    Werner, H. B. et al. Proteolipid protein is required for transport of sirtuin 2 into CNS myelin. J. Neurosci. 27, 7717–7730 (2007).

  35. 35

    Southwood, C. M., Peppi, M., Dryden, S., Tainsky, M. A. & Gow, A. Microtubule deacetylases, SirT2 and HDAC6, in the nervous system. Neurochem. Res. 32, 187–195 (2007).

  36. 36

    Li, W. et al. Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendroglial protein that decelerates cell differentiation through deacetylating alpha-tubulin. J. Neurosci. 27, 2606–2616 (2007).

  37. 37

    Zhao, S. et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000–1004 (2010).

  38. 38

    Kassmann, C. M. et al. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nature Genet. 39, 969–976 (2007).

  39. 39

    Gravel, M. et al. 2′,3′-cyclic nucleotide 3′-phosphodiesterase: a novel RNA-binding protein that inhibits protein synthesis. J. Neurosci. Res. 87, 1069–1079 (2009).

  40. 40

    Lee, J., Gravel, M., Zhang, R., Thibault, P. & Braun, P. E. Process outgrowth in oligodendrocytes is mediated by CNP, a novel microtubule assembly myelin protein. J. Cell. Biol. 170, 661–673 (2005).

  41. 41

    Readhead, C., Schneider, A., Griffiths, I. & Nave, K. A. Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 12, 583–595 (1994).

  42. 42

    Kagawa, T. et al. Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene. Neuron 13, 427–442 (1994).

  43. 43

    Simons, M. et al. Overexpression of the myelin proteolipid protein leads to accumulation of cholesterol and proteolipid protein in endosomes/lysosomes: implications for Pelizaeus–Merzbacher disease. J. Cell Biol. 157, 327–336 (2002).

  44. 44

    Anderson, T. J. et al. Late-onset neurodegeneration in mice with increased dosage of the proteolipid protein gene. J. Comp. Neurol. 394, 506–519 (1998).

  45. 45

    Ip, C. W. et al. Immune cells contribute to myelin degeneration and axonopathic changes in mice overexpressing proteolipid protein in oligodendrocytes. J. Neurosci. 26, 8206–8216 (2006). The finding that a primary defect of myelinating oligodendrocytes triggers a T-cell-mediated immune response that contributes to disease severity (see also ref. 38).

  46. 46

    Kroner, A., Ip, C. W., Thalhammer, J., Nave, K. A. & Martini, R. Ectopic T-cell specificity and absence of perforin and granzyme B alleviate neural damage in oligodendrocyte mutant mice. Am. J. Pathol. 176, 549–555 (2010).

  47. 47

    Edgar, J. M. et al. Demyelination and axonal preservation in a transgenic mouse model of Pelizaeus–Merzbacher disease. EMBO Mol. Med. 2, 42–50 (2010).

  48. 48

    Mayatepek, E., Baumann, M., Meissner, T., Hanefeld, F. & Korenke, G. C. Role of leukotrienes as indicators of the inflammatory demyelinating reaction in x-linked cerebral adrenoleukodystrophy. J. Neurol. 250, 1259–1260 (2003).

  49. 49

    Compston, A. & Coles, A. Multiple sclerosis. Lancet 372, 1502–1517 (2008).

  50. 50

    Rudick, R. A. & Trapp, B. D. Gray-matter injury in multiple sclerosis. New Engl. J. Med. 361, 1505–1506 (2009).

  51. 51

    Trapp, B. D. & Nave, K. A. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247–269 (2008).

  52. 52

    Trapp, B. D. & Stys, P. K. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 8, 280–291 (2009).

  53. 53

    Garbern, J. Y. Pelizaeus–Merzbacher disease: genetic and cellular pathogenesis. Cell Mol. Life Sci. 64, 50–65 (2007).

  54. 54

    Woodward, K. J. The molecular and cellular defects underlying Pelizaeus–Merzbacher disease. Expert Rev. Mol. Med. 10, e14 (2008).

  55. 55

    Uhlenberg, B. et al. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus–Merzbacher-like disease. Am. J. Hum. Genet. 75, 251–260 (2004).

  56. 56

    Maglione, M. et al. Oligodendrocytes in mouse corpus callosum are coupled via gap junction channels formed by connexin47 and connexin32. Glia 58, 1104–1117 (2010).

  57. 57

    Henneke, M. et al. GJA12 mutations are a rare cause of Pelizaeus–Merzbacher-like disease. Neurology 70, 748–754 (2008).

  58. 58

    Johnson, A. B. & Brenner, M. Alexander's disease: clinical, pathologic, and genetic features. J. Child Neurol. 18, 625–632 (2003).

  59. 59

    van der Knaap, M. S. et al. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann. Neurol. 51, 264–270 (2002).

  60. 60

    Dietrich, J. et al. EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nature Med. 11, 277–283 (2005).

  61. 61

    Baes, M. & Aubourg, P. Peroxisomes, myelination, and axonal integrity in the CNS. Neuroscientist 15, 367–379 (2009).

  62. 62

    Nave, K. A., Sereda, M. W. & Ehrenreich, H. Mechanisms of disease: inherited demyelinating neuropathies—from basic to clinical research. Nature Clin. Pract. Neurol. 3, 453–464 (2007).

  63. 63

    Suter, U. & Scherer, S. S. Disease mechanisms in inherited neuropathies. Nature Rev. Neurosci. 4, 714–726 (2003).

  64. 64

    De Jonghe, P. et al. The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot–Marie–Tooth phenotype. Brain 122, 281–290 (1999). A mutation of a myelin gene is found to cause the 'axonal form' of CMT disease, which uncouples Schwann-cell functions in myelination and axonal preservation.

  65. 65

    Hakak, Y. et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc. Natl Acad. Sci. USA 98, 4746–4751 (2001).

  66. 66

    Fields, R. D. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 31, 361–370 (2008).

  67. 67

    Bengtsson, S. L. et al. Extensive piano practicing has regionally specific effects on white matter development. Nature Neurosci. 8, 1148–1150 (2005).

  68. 68

    Stevens, B. & Fields, R. D. Response of Schwann cells to action potentials in development. Science 287, 2267–2271 (2000).

  69. 69

    Barres, B. A. & Raff, M. C. Proliferation of oligodendrocyte precursor cells depends on electrical activity in axons. Nature 361, 258–260 (1993).

  70. 70

    Stevens, B., Porta, S., Haak, L. L., Gallo, V. & Fields, R. D. Adenosine: a neuron–glial transmitter promoting myelination in the CNS in response to action potentials. Neuron 36, 855–868 (2002).

  71. 71

    Sanchez, I., Hassinger, L., Paskevich, P. A., Shine, H. D. & Nixon, R. A. Oligodendroglia regulate the regional expansion of axon caliber and local accumulation of neurofilaments during development independently of myelin formation. J. Neurosci. 16, 5095–5105 (1996).

  72. 72

    Sanchez, I. et al. Local control of neurofilament accumulation during radial growth of myelinating axons in vivo. Selective role of site-specific phosphorylation. J. Cell Biol. 151, 1013–1024 (2000).

  73. 73

    Bergles, D. E., Roberts, J. D., Somogyi, P. & Jahr, C. E. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405, 187–191 (2000). The discovery that unmyelinated axons make (transient) synaptic contact with the precursor cells of myelin-forming oligodendrocytes.

  74. 74

    Kukley, M., Capetillo-Zarate, E. & Dietrich, D. Vesicular glutamate release from axons in white matter. Nature Neurosci. 10, 311–320 (2007).

  75. 75

    Káradóttir, R., Cavelier, P., Bergersen, L. H. & Attwell, D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438, 1162–1166 (2005).

  76. 76

    Micu, I. et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439, 988–992 (2006).

  77. 77

    McGee, A. W., Yang, Y., Fischer, Q. S., Daw, N. W. & Strittmatter, S. M. Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science 309, 2222–2226 (2005).

  78. 78

    Budel, S. et al. Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth. J. Neurosci. 28, 13161–13172 (2008).

  79. 79

    Gregoriou, G. G., Gotts, S. J., Zhou, H. & Desimone, R. Long-range neural coupling through synchronization with attention. Prog. Brain Res. 176, 35–45 (2009).

  80. 80

    Dan, Y. & Poo, M. M. Spike timing-dependent plasticity of neural circuits. Neuron 44, 23–30 (2004).

  81. 81

    Toonen, R. F. et al. Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size. Proc. Natl Acad. Sci. USA 103, 18332–18337 (2006).

  82. 82

    Griffiths, I. et al. Current concepts of PLP and its role in the nervous system. Microsc. Res. Tech. 41, 344–358 (1998).

  83. 83

    Richardson, W. D., Kessaris, N. & Pringle, N. Oligodendrocyte wars. Nature Rev. Neurosci. 7, 11–18 (2006).

  84. 84

    Kukley, M., Nishiyama, A. & Dietrich, D. The fate of synaptic input to NG2 glial cells: neurons specifically downregulate transmitter release onto differentiating oligodendroglial cells. J. Neurosci. 30, 8320–8331 (2010).

  85. 85

    Jahn, O., Tenzer, S. & Werner, H. B. Myelin proteomics: molecular anatomy of an insulating sheath. Mol. Neurobiol. 40, 55–72 (2009).

  86. 86

    Saher, G. et al. High cholesterol level is essential for myelin membrane growth. Nature Neurosci. 8, 468–475 (2005).

  87. 87

    Michailov, G. V. et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700–703 (2004).

  88. 88

    Taveggia, C., Feltri, M. L. & Wrabetz, L. Signals to promote myelin formation and repair. Nature Rev. Neurol. 6, 276–287 (2010).

  89. 89

    Pertusa, M., Morenilla-Palao, C., Carteron, C., Viana, F. & Cabedo, H. Transcriptional control of cholesterol biosynthesis in Schwann cells by axonal neuregulin 1. J. Biol. Chem. 282, 28768–28778 (2007).

  90. 90

    Goebbels, S. et al. Elevated phosphatidylinositol 3,4,5-trisphosphate in glia triggers cell-autonomous membrane wrapping and myelination. J. Neurosci. 30, 8953–8964 (2010).

  91. 91

    Cotter, L. et al. Dlg1-PTEN interaction regulates myelin thickness to prevent damaging peripheral nerve overmyelination. Science 328, 1415–1418 (2010).

  92. 92

    Bremer, J. et al. Axonal prion protein is required for peripheral myelin maintenance. Nature Neurosci. 13, 310–318 (2010).

  93. 93

    Chan, J. R. et al. NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes. Neuron 43, 183–191 (2004).

  94. 94

    Brinkmann, B. G. et al. Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron 59, 581–595 (2008).

  95. 95

    Carson, M. J., Behringer, R. R., Brinster, R. L. & McMorris, F. A. Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 10, 729–740 (1993).

  96. 96

    Ishibashi, T. et al. Astrocytes promote myelination in response to electrical impulses. Neuron 49, 823–832 (2006).

  97. 97

    Flores, A. I. et al. Constitutively active Akt induces enhanced myelination in the CNS. J. Neurosci. 28, 7174–7183 (2008).

  98. 98

    Rosenberg, S. S., Kelland, E. E., Tokar, E., De la Torre, A. R. & Chan, J. R. The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation. Proc. Natl Acad. Sci. USA 105, 14662–14667 (2008). This reports that cultured oligodendrocytes can 'myelinate' chemically fixed axons, which implies that only limited bidirectional signalling is required.

  99. 99

    Charles, P. et al. Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule. Proc. Natl Acad. Sci. USA 97, 7585–7590 (2000).

Download references

Acknowledgements

I apologize to all colleagues whose important work could not be cited owing to space limitations. I thank S. Goebbels and H. Werner for help with figures, and J. Edgar and D. Dietrich for providing images. I also thank all members of my group as well as D. Attwell, P. Casaccia, J. Edgar, I. Griffiths, O. Peles, J. Salzer, S. Scherer, P. Stys and B. Trapp for discussions. Work in my laboratory is supported by the German Research Foundation (Center for Molecular Physiology of the Brain in Göttingen, SFB/TR43), the European Leukodystrophy Association, the Myelin Project, the German Federal Ministry of Education and Research (Leukonet) and the European Union (Sixth Framework Programme, Neuropromise; Seventh Framework Programme, Ngidd, Leukotreat).

Author information

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nave, K. Myelination and support of axonal integrity by glia. Nature 468, 244–252 (2010) doi:10.1038/nature09614

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.