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Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity

Nature Neuroscience volume 12, pages 839–847 (2009)Cite this article

Abstract

Notch signaling is central to vertebrate development, and analysis of Notch has provided important insights into pathogenetic mechanisms in the CNS and many other tissues. However, surprisingly little is known about the role of Notch in the development and pathology of Schwann cells and peripheral nerves. Using transgenic mice and cell cultures, we found that Notch has complex and extensive regulatory functions in Schwann cells. Notch promoted the generation of Schwann cells from Schwann cell precursors and regulated the size of the Schwann cell pool by controlling proliferation. Notch inhibited myelination, establishing that myelination is subject to negative transcriptional regulation that opposes forward drives such as Krox20. Notably, in the adult, Notch dysregulation resulted in demyelination; this finding identifies a signaling pathway that induces myelin breakdown in vivo. These findings are relevant for understanding the molecular mechanisms that control Schwann cell plasticity and underlie nerve pathology, including demyelinating neuropathies and tumorigenesis.

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Figure 1: Notch signaling is not involved in the generation of SCPs from neural crest cells.
Figure 2: Notch signaling pathway molecules are expressed at different stages in the Schwann cell lineage.
Figure 3: Notch drives Schwann cell generation from SCPs.
Figure 4: Notch signaling controls the proliferation of immature Schwann cells.
Figure 5: Notch signaling inhibits myelination.
Figure 6: Notch inactivation in Schwann cells leads to RBPJ-independent premature myelination.
Figure 7: Notch promotes demyelination in injured nerves.
Figure 8: Notch activation induces extensive demyelination in vitro and in vivo. (a) Notch activation results in extensive myelin breakdown in co-cultures of neurons and Schwann cells.

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Acknowledgements

This work was funded by a Wellcome Trust Programme Grant to K.R.J., R.M. and D.B.P., a Wellcome Trust Project grant to K.R.J. and R.M. and grants from the US National Institutes of Health to M.L.F. and L.W.

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, University College London, London, UK

    Ashwin Woodhoo, Maria B Duran Alonso, Anna Droggiti, Mark Turmaine, Daniel K Wilton, Rhona Mirsky & Kristján R Jessen

  2. DIBIT, San Raffaele Scientific Institute, Milan, Italy

    Maurizio D'Antonio, M Laura Feltri & Lawrence Wrabetz

  3. Peninsula Medical School, Plymouth, UK

    David B Parkinson

  4. Department of Medicine, University College London, London, UK

    Raya Al-Shawi & Paul Simons

  5. Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Jie Shen

  6. National Institute for Medical Research, London, UK

    Francois Guillemot

  7. Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland

    Freddy Radtke

  8. Department of Cell Biology and Genetics, Erasmus MC, Rotterdam, The Netherlands

    Dies Meijer

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  1. Ashwin Woodhoo
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Contributions

A.W. carried out all the experiments with the exception of cAMP myelination assays and PCR analyses, which were performed by M.B.D.A. A.W. was helped by A.D. in in situ hybridization experiments, by M.T. in EM sectioning, by M.D. in FACS, by D.B.P. in in vitro inhibitor experiments and by D.K.W. in animal husbandry. R.A.-S. and P.S. generated Hes1−/−Hes5−/− cells from frozen embryos. J.S., F.G., F.R., D.M., M.L.F. and L.W. provided the mice. A.W. generated all the figures. A.W., R.M. and K.R.J. designed the experiments. K.R.J., A.W. and R.M. wrote the manuscript.

Corresponding author

Correspondence to Kristján R Jessen.

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Woodhoo, A., Alonso, M., Droggiti, A. et al. Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat Neurosci 12, 839–847 (2009). https://doi.org/10.1038/nn.2323

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