Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

LINGO-1 negatively regulates myelination by oligodendrocytes


The control of myelination by oligodendrocytes in the CNS is poorly understood. Here we show that LINGO-1 is an important negative regulator of this critical process. LINGO-1 is expressed in oligodendrocytes. Attenuation of its function by dominant-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation and increased myelination competence. Attenuation of LINGO-1 results in downregulation of RhoA activity, which has been implicated in oligodendrocyte differentiation. Conversely, overexpression of LINGO-1 leads to activation of RhoA and inhibition of oligodendrocyte differentiation and myelination. Treatment of oligodendrocyte and neuron cocultures with LINGO-1-Fc resulted in highly developed myelinated axons that have internodes and well-defined nodes of Ranvier. The contribution of LINGO-1 to myelination was verified in vivo through the analysis of LINGO-1 knockout mice. The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGO-1 knockout indicate that LINGO-1 signaling may be critical for CNS myelination.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: LINGO-1 is expressed in oligodendrocytes.
Figure 2: LINGO-1 antagonists promote oligodendrocyte differentiation.
Figure 3: LINGO-1 antagonists regulate RhoA and Fyn.
Figure 4: LINGO-1 antagonists promote axonal myelination by oligodendrocytes.
Figure 5: Oligodendrocyte differentiation and myelination in LINGO-1 knockout mice.


  1. Edgar, J.M. & Garbern, J. The myelinated axon is dependent on the myelinating cell for support and maintenance: molecules involved. J. Neurosci. Res. 76, 593–598 (2004).

    CAS  Article  Google Scholar 

  2. Garbay, B., Heape, A.M., Sargueil, F. & Cassagne, C. Myelin synthesis in the peripheral nervous system. Prog. Neurobiol. 61, 267–304 (2000).

    CAS  Article  Google Scholar 

  3. Trapp, B.D., Ransohoff, R. & Rudick, R. Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr. Opin. Neurol. 12, 295–302 (1999).

    CAS  Article  Google Scholar 

  4. Trapp, B.D., Bo, L., Mork, S. & Chang, A. Pathogenesis of tissue injury in MS lesions. J. Neuroimmunol. 98, 49–56 (1999).

    CAS  Article  Google Scholar 

  5. Villagra, N.T. et al. PML bodies in reactive sensory ganglion neurons of the Guillain-Barre syndrome. Neurobiol. Dis. 16, 158–168 (2004).

    CAS  Article  Google Scholar 

  6. Kiewe, P. et al. Progressive multifocal leukoencephalopathy with detection of JC virus in a patient with chronic lymphocytic leukemia parallel to onset of fludarabine therapy. Leuk. Lymphoma 44, 1815–1818 (2003).

    Article  Google Scholar 

  7. Kolodny, E.H. Dysmyelinating and demyelinating conditions in infancy. Curr. Opin. Neurol. Neurosurg. 6, 379–386 (1993).

    CAS  PubMed  Google Scholar 

  8. Salvati, S., Attorri, L., Avellino, C., Di Biase, A. & Sanchez, M. Diet, lipids and brain development. Dev. Neurosci. 22, 481–487 (2000).

    CAS  Article  Google Scholar 

  9. Stoffel, W. & Bosio, A. Myelin glycolipids and their functions. Curr. Opin. Neurobiol. 7, 654–661 (1997).

    CAS  Article  Google Scholar 

  10. Friede, R.L. Relation between myelin sheath thickness, internode geometry, and sheath resistance. Exp. Neurol. 92, 234–247 (1986).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  13. Wang, S. et al. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 21, 63–75 (1998).

    Article  Google Scholar 

  14. Vartanian, T., Goodearl, A., Viehover, A. & Fischbach, G. Axonal neuregulin signals cells of the oligodendrocyte lineage through activation of HER4 and Schwann cells through HER2 and HER3. J. Cell Biol. 137, 211–220 (1997).

    CAS  Article  Google Scholar 

  15. Givogri, M.I. et al. Central nervous system myelination in mice with deficient expression of Notch1 receptor. J. Neurosci. Res. 67, 309–320 (2002).

    CAS  Article  Google Scholar 

  16. Garratt, A.N., Britsch, S. & Birchmeier, C. Neuregulin, a factor with many functions in the life of a Schwann cell. Bioessays 22, 987–996 (2000).

    CAS  Article  Google Scholar 

  17. Liang, X., Draghi, N.A. & Resh, M.D. Signaling from integrins to Fyn to Rho family GTPases regulates morphologic differentiation of oligodendrocytes. J. Neurosci. 24, 7140–7149 (2004).

    CAS  Article  Google Scholar 

  18. Mi, S. et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat. Neurosci. 7, 221–228 (2004).

    CAS  Article  Google Scholar 

  19. Shao, Z. et al. Taj/Troy, an orphan TNF receptor family member, interacts with the Nogo-66 receptor and regulates axonal regeneration. Neuron 45, 353–359 (2005).

    CAS  Article  Google Scholar 

  20. Park, J. et al. A TNF receptor family member TROY is a co-receptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors. Neuron 45, 345–351 (2005).

    CAS  Article  Google Scholar 

  21. Osterhout, D.J., Wolven, A., Wolf, R.M., Resh, M.D. & Chao, M.V. Morphological differentiation of oligodendrocytes requires activation of Fyn tyrosine kinase. J. Cell Biol. 145, 1209–1218 (1999).

    CAS  Article  Google Scholar 

  22. Svenningsen, A.F., Shan, W.S., Colman, D.R. & Pedraza, L. Rapid method for culturing embryonic neuron-glial cell cocultures. J. Neurosci. Res. 72, 565–573 (2003).

    CAS  Article  Google Scholar 

  23. Sperber, B.R. & McMorris, F.A. Fyn tyrosine kinase regulates oligodendroglial cell development but is not required for morphological differentiation of oligodendrocytes. J. Neurosci. Res. 63, 303–312 (2001).

    CAS  Article  Google Scholar 

  24. Wolf, R.M., Wilkes, J.J., Chao, M.V. & Resh, M.D. Tyrosine phosphorylation of p190 RhoGAP by Fyn regulates oligodendrocyte differentiation. J. Neurobiol. 49, 62–78 (2001).

    CAS  Article  Google Scholar 

  25. Sperber, B.R. et al. A unique role for Fyn in CNS myelination. J. Neurosci. 21, 2039–2047 (2001).

    CAS  Article  Google Scholar 

  26. Kramer, E.M., Klein, C., Koch, T., Boytinck, M. & Trotter, J. Compartmentation of Fyn kinase with glycosylphosphatidylinositol-anchored molecules in oligodendrocytes facilitates kinase activation during myelination. J. Biol. Chem. 274, 29042–29049 (1999).

    CAS  Article  Google Scholar 

  27. Melendez-Vasquez, C.V., Einheber, S. & Salzer, J.L. Rho kinase regulates schwann cell myelination and formation of associated axonal domains. J. Neurosci. 24, 3953–3963 (2004).

    CAS  Article  Google Scholar 

  28. Kaplan, M.R. et al. Induction of sodium channel clustering by oligodendrocytes. Nature 386, 724–728 (1997).

    CAS  Article  Google Scholar 

  29. Bhat, R.V. et al. Expression of the APC tumor suppressor protein in oligodendroglia. Glia 17, 169–174 (1996).

    CAS  Article  Google Scholar 

  30. Rubinson, D.A. et al. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat. Genet. 33, 401–406 (2003).

    CAS  Article  Google Scholar 

  31. Partadiredja, G., Miller, R. & Oorschot, D.E. The number, size, and type of axons in rat subcortical white matter on left and right sides: a stereological, ultrastructural study. J. Neurocytol. 32, 1165–1179 (2003).

    Article  Google Scholar 

  32. Li, C., Trapp, B., Ludwin, S., Peterson, A. & Roder, J. Myelin associated glycoprotein modulates glia-axon contact in vivo. J. Neurosci. Res. 51, 210–217 (1998).

    CAS  Article  Google Scholar 

  33. Zhang, Y., Muyrers, J.P., Testa, G. & Stewart, A.F. DNA cloning by homologous recombination in Escherichia coli. Nat. Biotechnol. 18, 1314–1317 (2000).

    CAS  Article  Google Scholar 

Download references


We thank J. Mason and other LINGO-1 team members and the research management team from Biogenidec for discussions.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Sha Mi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mi, S., Miller, R., Lee, X. et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci 8, 745–751 (2005).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing