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

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

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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.

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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.

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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.

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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

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  1. Ruth M Stassart
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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.

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The authors declare no competing financial interests.

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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

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