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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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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. Woodhoo, A. & Sommer, L. Development of the Schwann cell lineage: from the neural crest to the myelinated nerve. Glia 56, 1481–1490 (2008).

    Article  Google Scholar 

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

    Article  Google Scholar 

  4. Louvi, A. & Artavanis-Tsakonas, S. Notch signalling in vertebrate neural development. Nat. Rev. Neurosci. 7, 93–102 (2006).

    Article  CAS  Google Scholar 

  5. Yoon, K. & Gaiano, N. Notch signaling in the mammalian central nervous system: insights from mouse mutants. Nat. Neurosci. 8, 709–715 (2005).

    Article  CAS  Google Scholar 

  6. Lasky, J.L. & Wu, H. Notch signaling, brain development and human disease. Pediatr. Res. 57, 104R–109R (2005).

    Article  Google Scholar 

  7. Bothwell, M. & Giniger, E. Alzheimer's disease: neurodevelopment converges with neurodegeneration. Cell 102, 271–273 (2000).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  9. Scherer, S.S. & Salzer, J.L. Axonal-Schwann cell interactions during peripheral nerve degeneration and regeneration. in Glial Cell Development: Basic Principles and Clinical Relevance (eds. Jessen, K.R. & Richardson, W.D.) 299–330 (Oxford, New York, 2001).

    Google Scholar 

  10. Müller, H.W. & Stoll, G. Nerve injury and regeneration: basic insights and therapeutic interventions. Curr. Opin. Neurol. 11, 557–562 (1998).

    Article  Google Scholar 

  11. Kubu, C.J. et al. Developmental changes in Notch1 and numb expression mediated by local cell-cell interactions underlie progressively increasing delta sensitivity in neural crest stem cells. Dev. Biol. 244, 199–214 (2002).

    Article  CAS  Google Scholar 

  12. Wakamatsu, Y., Maynard, T.M. & Weston, J.A. Fate determination of neural crest cells by NOTCH-mediated lateral inhibition and asymmetrical cell division during gangliogenesis. Development 127, 2811–2821 (2000).

    CAS  Google Scholar 

  13. Morrison, S.J. et al. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 101, 499–510 (2000).

    Article  CAS  Google Scholar 

  14. Bray, S.J. Notch signalling: a simple pathway becomes complex. Nat. Rev. Mol. Cell Biol. 7, 678–689 (2006).

    Article  CAS  Google Scholar 

  15. Taylor, M.K., Yeager, K. & Morrison, S.J. Physiological Notch signaling promotes gliogenesis in the developing peripheral and central nervous systems. Development 134, 2435–2447 (2007).

    Article  CAS  Google Scholar 

  16. Jessen, K.R., Morgan, L., Stewart, H.J.S. & Mirsky, R. Three markers of adult non-myelin-forming Schwann cells, 217c (Ran-1), A5E3 and GFAP: development and regulation by neuron–Schwann cell interactions. Development 109, 91–103 (1990).

    CAS  PubMed  Google Scholar 

  17. Meier, C., Parmantier, E., Brennan, A., Mirsky, R. & Jessen, K.R. Developing Schwann cells acquire the ability to survive without axons by establishing an autocrine circuit involving insulin-like growth factor, neurotrophin-3 and platelet-derived growth factor-BB. J. Neurosci. 19, 3847–3859 (1999).

    Article  CAS  Google Scholar 

  18. Brennan, A. et al. Endothelins control the timing of Schwann cell generation in vitro and in vivo. Dev. Biol. 227, 545–557 (2000).

    Article  CAS  Google Scholar 

  19. Dong, Z. et al. Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation and maturation of rat Schwann cell precursors. Neuron 15, 585–596 (1995).

    Article  CAS  Google Scholar 

  20. 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 

  21. Stewart, H.J., Morgan, L., Jessen, K.R. & Mirsky, R. Changes in DNA synthesis rate in the Schwann cell lineage in vivo are correlated with the precursor-Schwann cell transition and myelination. Eur. J. Neurosci. 5, 1136–1144 (1993).

    Article  CAS  Google Scholar 

  22. Yu, W.M., Feltri, M.L., Wrabetz, L., Strickland, S. & Chen, Z.L. Schwann cell–specific ablation of laminin gamma1 causes apoptosis and prevents proliferation. J. Neurosci. 25, 4463–4472 (2005).

    Article  CAS  Google Scholar 

  23. Winseck, A.K. & Oppenheim, R.W. An in vivo analysis of Schwann cell programmed cell death in embryonic mice: the role of axons, glial growth factor, and the pro-apoptotic gene Bax. Eur. J. Neurosci. 24, 2105–2117 (2006).

    Article  Google Scholar 

  24. Webster, H.D., Martin, R. & O'Connell, M.F. The relationships between interphase Schwann cells and axons before myelination: a quantitative electron microscopic study. Dev. Biol. 32, 401–416 (1973).

    Article  CAS  Google Scholar 

  25. Topilko, P. et al. Krox-20 controls myelination in the peripheral nervous system. Nature 371, 796–799 (1994).

    Article  CAS  Google Scholar 

  26. Parkinson, D.B. et al. Regulation of the myelin gene periaxin provides evidence for Krox-20–independent myelin-related signaling in Schwann cells. Mol. Cell. Neurosci. 23, 13–27 (2003).

    Article  CAS  Google Scholar 

  27. Parkinson, D.B. et al. c-Jun is a negative regulator of myelination. J. Cell Biol. 181, 625–637 (2008).

    Article  CAS  Google Scholar 

  28. Lemke, G. & Chao, M. Axons regulate Schwann cell expression of the major myelin and NGF receptor genes. Development 102, 499–504 (1988).

    CAS  PubMed  Google Scholar 

  29. Morgan, L., Jessen, K.R. & Mirsky, R. The effects of cAMP on differentiation of cultured Schwann cells: progression from an early phenotype (04+) to a myelin phenotype (P0+, GFAP−, N-CAM−, NGF receptor−) depends on growth inhibition. J. Cell Biol. 112, 457–467 (1991).

    Article  CAS  Google Scholar 

  30. Luo, D., Renault, V.M. & Rando, T.A. The regulation of Notch signaling in muscle stem cell activation and postnatal myogenesis. Semin. Cell Dev. Biol. 16, 612–622 (2005).

    Article  CAS  Google Scholar 

  31. Martinez Arias, A., Zecchini, V. & Brennan, K. CSL-independent Notch signaling: a checkpoint in cell fate decisions during development. Curr. Opin. Genet. Dev. 12, 524–533 (2002).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Svaren, J. & Meijer, D. The molecular machinery of myelin gene transcription in Schwann cells. Glia 56, 1541–1551 (2008).

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. John, G.R. et al. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat. Med. 8, 1115–1121 (2002).

    Article  CAS  Google Scholar 

  38. Li, Y. et al. Notch and Schwann cell transformation. Oncogene 23, 1146–1152 (2004).

    Article  CAS  Google Scholar 

  39. Hatakeyama, J. et al. Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131, 5539–5550 (2004).

    Article  CAS  Google Scholar 

  40. Tanigaki, K. et al. Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nat. Immunol. 3, 443–450 (2002).

    Article  CAS  Google Scholar 

  41. 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 

  42. Radtke, F. et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547–558 (1999).

    Article  CAS  Google Scholar 

  43. Yang, X. et al. Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway. Dev. Biol. 269, 81–94 (2004).

    Article  CAS  Google Scholar 

  44. Feltri, M.L. et al. P0-Cre transgenic mice for inactivation of adhesion molecules in Schwann cells. Ann. NY Acad. Sci. 883, 116–123 (1999).

    Article  CAS  Google Scholar 

  45. Sharghi-Namini, S. et al. The structural and functional integrity of peripheral nerves depends on the glial-derived signal desert hedgehog. J. Neurosci. 26, 6364–6376 (2006).

    Article  CAS  Google Scholar 

  46. D'Antonio, M. et al. TGFbeta type II receptor signaling controls Schwann cell death and proliferation in developing nerves. J. Neurosci. 26, 8417–8427 (2006).

    Article  CAS  Google Scholar 

  47. D'Antonio, M. et al. Gene profiling and bioinformatic analysis of Schwann cell embryonic development and myelination. Glia 53, 501–515 (2006).

    Article  Google Scholar 

  48. Rangarajan, A. et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 20, 3427–3436 (2001).

    Article  CAS  Google Scholar 

  49. Jessen, K.R., Morgan, L., Brammer, M. & Mirsky, R. Galactocerebroside is expressed by non-myelin-forming Schwann cells in situ. J. Cell Biol. 101, 1135–1143 (1985).

    Article  CAS  Google Scholar 

  50. Morgan, L., Jessen, K.R. & Mirsky, R. Negative regulation of the P0 gene in Schwann cells: suppression of P0 mRNA and protein induction in cultured Schwann cells by FGF2 and TGF beta 1, TGF beta 2 and TGF beta 3. Development 120, 1399–1409 (1994).

    CAS  PubMed  Google Scholar 

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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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