Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

A role for Schwann cell–derived neuregulin-1 in remyelination

Nature Neuroscience volume 16, pages 48–54 (2013)Cite this article

Subjects

Abstract

After peripheral nerve injury, axons regenerate and become remyelinated by resident Schwann cells. However, myelin repair never results in the original myelin thickness, suggesting insufficient stimulation by neuronal growth factors. Upon testing this hypothesis, we found that axonal neuregulin-1 (NRG1) type III and, unexpectedly, also NRG1 type I restored normal myelination when overexpressed in transgenic mice. This led to the observation that Wallerian degeneration induced de novo NRG1 type I expression in Schwann cells themselves. Mutant mice lacking a functional Nrg1 gene in Schwann cells are fully myelinated but exhibit impaired remyelination in adult life. We suggest a model in which loss of axonal contact triggers denervated Schwann cells to transiently express NRG1 as an autocrine/paracrine signal that promotes Schwann cell differentiation and remyelination.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Axonal NRG1 type I promotes efficient remyelination.
Figure 2: After injury, NRG1 expression is induced in Schwann cells.
Figure 3: Schwann cell NRG1 type I is regulated by axonal NRG1 type III.
Figure 4: Schwann cell–derived NRG1 is required for efficient remyelination.
Figure 5: Schwann cells require NRG1 expression for timely redifferentiation.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Nave, K.A. Myelination and support of axonal integrity by glia. Nature 468, 244–252 (2010).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Taveggia, C. et al. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47, 681–694 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Birchmeier, C. & Nave, K.A. Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation. Glia 56, 1491–1497 (2008).

    Article  Google Scholar 

  8. Falls, D.L. Neuregulins and the neuromuscular system: 10 years of answers and questions. J. Neurocytol. 32, 619–647 (2003).

    Article  CAS  Google Scholar 

  9. Bosse, F. Extrinsic cellular and molecular mediators of peripheral axonal regeneration. Cell Tissue Res. 349, 5–14 (2012).

    Article  CAS  Google Scholar 

  10. Atanosoki, S. et al. ErbB2 signaling in Schwann cells is mostly dispensable for maintenance of myelinated peripheral nerves and proliferation of adult Schwann cells after injury. J. Neurosci. 26, 2124–2131 (2006).

    Article  Google Scholar 

  11. Fricker, F.R. et al. Axonally derived neuregulin-1 is required for remyelination and regeneration after nerve injury in adulthood. J. Neurosci. 31, 3225–3233 (2011).

    Article  CAS  Google Scholar 

  12. Fricker, F.R. & Bennett, D.L. The role of neuregulin-1 in the response to nerve injury. Future Neurol. 6, 809–822 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Schröder, J.M. Altered ratio between axon diameter and myelin sheath thickness in regenerated nerve fibers. Brain Res. 45, 49–65 (1972).

    Article  Google Scholar 

  15. Jaegle, M. et al. The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development. Genes Dev. 17, 1380–1391 (2003).

    Article  CAS  Google Scholar 

  16. Li, L. et al. The breast proto-oncogene, HRGalpha regulates epithelial proliferation and lobuloalveolar development in the mouse mammary gland. Oncogene 21, 4900–4907 (2002).

    Article  CAS  Google Scholar 

  17. Fawcett, J.W. & Keynes, R.J. Peripheral nerve regeneration. Annu. Rev. Neurosci. 13, 43–60 (1990).

    Article  CAS  Google Scholar 

  18. Welcher, A.A., Suter, U., De Leon, M., Bitler, C.M. & Shooter, E.M. Molecular approaches to nerve regeneration. Phil. Trans. R. Soc. Lond. B 331, 295–301 (1991).

    Article  CAS  Google Scholar 

  19. Bermingham-McDonogh, O., Xu, Y.T., Marchionni, M.A. & Scherer, S.S. Neuregulin expression in PNS neurons: isoforms and regulation by target interactions. Mol. Cell. Neurosci. 10, 184–195 (1997).

    Article  CAS  Google Scholar 

  20. Carroll, S.L., Miller, M.L., Frohnert, P.W., Kim, S.S. & Corbett, J.A. Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J. Neurosci. 17, 1642–1659 (1997).

    Article  CAS  Google Scholar 

  21. Wolpowitz, D. et al. Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses. Neuron 25, 79–91 (2000).

    Article  CAS  Google Scholar 

  22. Myers, R.R. et al. Inhibition of p38 MAP kinase activity enhances axonal regeneration. Exp. Neurol. 184, 606–614 (2003).

    Article  CAS  Google Scholar 

  23. Mirsky, R. et al. Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation. J. Peripher. Nerv. Syst. 13, 122–135 (2008).

    Article  Google Scholar 

  24. Jessen, K.R. & Mirsky, R. Negative regulation of myelination: relevance for development, injury, and demyelinating disease. Glia 56, 1552–1565 (2008).

    Article  Google Scholar 

  25. Höke, A. Mechanisms of disease: what factors limit the success of peripheral nerve regeneration in humans? Nat. Clin. Pract. Neurol. 2, 448–454 (2006).

    Article  Google Scholar 

  26. Chen, Z.L., Yu, W.M. & Strickland, S. Peripheral regeneration. Annu. Rev. Neurosci. 30, 209–233 (2007).

    Article  Google Scholar 

  27. Napoli, I. et al. A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron 73, 729–742 (2012).

    Article  CAS  Google Scholar 

  28. Loeb, J.A., Khurana, T.S., Robbins, J.T., Yee, A.G. & Fischbach, G.D. Expression patterns of transmembrane and released forms of neuregulin during spinal cord and neuromuscular synapse development. Development 126, 781–791 (1999).

    CAS  PubMed  Google Scholar 

  29. Rosenbaum, C. et al. Schwann cells express NDF and SMDF/n-ARIA mRNAs, secrete neuregulin, and show constitutive activation of erbB3 receptors: evidence for a neuregulin autocrine loop. Exp. Neurol. 148, 604–615 (1997).

    Article  CAS  Google Scholar 

  30. Stonecypher, M.S., Chaudhury, A.R., Byer, S.J. & Carroll, S.L. Neuregulin growth factors and their ErbB receptors form a potential signaling network for schwannoma tumorigenesis. J. Neuropathol. Exp. Neurol. 65, 162–175 (2006).

    Article  CAS  Google Scholar 

  31. 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).

    Article  CAS  Google Scholar 

  32. Velanac, V. et al. Bace1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination. Glia 60, 203–217 (2012).

    Article  Google Scholar 

  33. Spiegel, I. et al. A central role for Necl4 (SynCAM4) in Schwann cell-axon interaction and myelination. Nat. Neurosci. 10, 861–869 (2007).

    Article  CAS  Google Scholar 

  34. Ghazvini, M. et al. A cell type-specific allele of the POU gene Oct-6 reveals Schwann cell autonomous function in nerve development and regeneration. EMBO J. 21, 4612–4620 (2002).

    Article  CAS  Google Scholar 

  35. Brockes, J.P., Fields, K.L. & Raff, M.C. Studies on cultured rat Schwann cells. I. Establishment of purified populations from cultures of peripheral nerve. Brain Res. 165, 105–118 (1979).

    Article  CAS  Google Scholar 

  36. Campenot, R.B. Development of sympathetic neurons in compartmentalized cultures. Il Local control of neurite growth by nerve growth factor. Dev. Biol. 93, 1–12 (1982).

    Article  CAS  Google Scholar 

  37. Kleitman, N., Wood, P.M. & Bunge, R.P. Tissue culture methods for the study of myelination. in Culturing Nerve Cells 2nd edn. (eds., Banker G.A. & Goslin, K.) 545–594 (MIT, 1998).

  38. Inserra, M.M., Bloch, D.A. & Terris, D.J. Functional indices for sciatic, peroneal, and posterior tibial nerve lesions in the mouse. Microsurgery 18, 119–124 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Birchmeier (Max Delbrück Center, Berlin) for providing NRG1 'floxed' mice, L. Role (Stony Brook University) for providing NRG1 type III mutants, and A. Fahrenholz for help with immunohistochemistry. This work was supported by grants from Deutsche Forschungsgemeinschaft Research Center Molecular Physiology of the Brain, European Commission FP7-201535 (Ngidd) to K.-A.N. and by the Association Francaise contre Les Myopathies (15037 to M.W.S.). M.W.S. and R.F. were supported by the German Ministry of Education and Research (BMBF, FKZ: 01ES0812 to M.W.S.). M.W.S. is funded through a Deutsche Forschungsgemeinschaft Heisenberg professorship. K.-A.N. is funded through a European Research Council Advanced Investigator grant.

Author information

Author notes

  1. Ruth M Stassart and Robert Fledrich: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany

    Ruth M Stassart, Robert Fledrich, Viktorija Velanac, Bastian G Brinkmann, Markus H Schwab, Michael W Sereda & Klaus-Armin Nave

  2. Department of Neuropathology, University of Göttingen, Göttingen, Germany

    Ruth M Stassart

  3. German Center for Neurodegenerative Diseases, Bonn, Germany

    Viktorija Velanac

  4. Department of Neurosurgery, Charité, University Medicine, Berlin, Germany

    Bastian G Brinkmann

  5. Department of Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

    Dies Meijer

  6. Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany

    Michael W Sereda

Authors
  1. Ruth M Stassart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Fledrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Viktorija Velanac
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bastian G Brinkmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Markus H Schwab
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dies Meijer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael W Sereda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Klaus-Armin Nave
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.M.S. and R.F. performed experiments. V.V. performed immunohistochemistry analyses. B.G.B. and D.M. generated transgenic mice. R.M.S., M.W.S., M.H.S. and K.-A.N. supervised the work. R.M.S., M.W.S. and K.-A.N. wrote the manuscript.

Corresponding authors

Correspondence to Michael W Sereda or Klaus-Armin Nave.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 2566 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stassart, R., Fledrich, R., Velanac, V. et al. A role for Schwann cell–derived neuregulin-1 in remyelination. Nat Neurosci 16, 48–54 (2013). https://doi.org/10.1038/nn.3281

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3281

This article is cited by

Search

Advanced search

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