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The origin and development of glial cells in peripheral nerves

Key Points

  • The Schwann cell precursor (SCP) represents the first step in the process of gliogenesis in growing nerves. In addition to generating Schwann cells, these cells are likely to provide essential trophic support to sensory and motor neurons and are necessary for the structural cohesion of peripheral nerves. They also have the potential to generate neurons and may be the source of the fibroblast population that is found in peripheral nerves.

  • In many ways our ideas about CNS and PNS glial cells have changed along a similar trajectory during recent years. In both cases, novel and unexpected glial functions have been determined and glia are increasingly recognized as sources of signals that are essential for the survival and function of neurons and other cells. Furthermore, the emerging idea that glial cells can act as multipotent progenitors seems to be true not only in the CNS, but also in the PNS, as SCPs, like radial glia, can give rise to unexpected lineages that were previously thought to arise from different sources.

  • Although a large number of molecules have now been implicated in the regulation of Schwann cell development, it is notable that our knowledge about postnatal events greatly exceeds what we know about the control of the embryonic phase of the lineage. Neuregulin 1, in particular the axon-associated type III isoform, has emerged as a signalling molecule of fundamental importance and considerable versatility, as it is likely to carry out different functions at different stages of the lineage. Another key regulator is SOX10, which is required for the gereration of Schwann cell precursors from the neural crest. Understanding the signals that regulate the appearance of glial differentiation in neural crest cells, and defining the role of positive and/or negative inductive signals or default mechanisms in this key event remain challenging areas. Another important step will be the clarification of the molecular regulators of myelination.

Abstract

During the development of peripheral nerves, neural crest cells generate myelinating and non-myelinating glial cells in a process that parallels gliogenesis from the germinal layers of the CNS. Unlike central gliogenesis, neural crest development involves a protracted embryonic phase devoted to the generation of, first, the Schwann cell precursor and then the immature Schwann cell, a cell whose fate as a myelinating or non-myelinating cell has yet to be determined. Embryonic nerves therefore offer a particular opportunity to analyse the early steps of gliogenesis from transient multipotent stem cells, and to understand how this process is integrated with organogenesis of peripheral nerves.

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Figure 1: The Schwann cell lineage.
Figure 2: The appearance of early cells in the Schwann cell lineage.
Figure 3: Some of the factors that have been implicated in the control of early Schwann cell development and myelination
Figure 4: Changes in phenotypic profile as cells progress through the embryonic Schwann cell lineage.
Figure 5: Cell and tissue relationships at key stages of Schwann cell development in rodents.

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References

  1. Reynolds, M. L., Fitzgerald, M. & Benowitz, L. I. GAP-43 expression in developing cutaneous and muscle nerves in the rat hindlimb. Neuroscience 41, 201–211 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Goodman, C. Mechanisms and molecules that control growth cone guidance. Annu. Rev. Neurosci. 19, 341–377 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Ziskind-Conhaim, L. Physiological and morphological changes in developing peripheral nerves of rat embryos. Brain Res. 470, 15–28 (1988).

    Article  CAS  PubMed  Google Scholar 

  4. Jessen, K. R. & Mirsky, R. in Myelin Biology and Disorders (ed. Lazzarini, R. A.) 329–359 (Elsevier, USA, 2004).

    Google Scholar 

  5. Grim, M., Halata, Z. & Franz, T. Schwann cells are not required for guidance of motor nerves in the hindlimb in Splotch mutant mouse embryos. Anat. Embryol. (Berl.) 186, 311–318 (1992).

    Article  CAS  Google Scholar 

  6. Riethmacher, D. et al. Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389, 725–730 (1997). Shows that in mice with a targeted mutation of the NRG1 receptor, ErbB3, Schwann cell precursors and Schwann cells are absent and there is increased non-autonomous cell death of motor and sensory neurons.

    Article  CAS  PubMed  Google Scholar 

  7. Woldeyesus, M. T. et al. Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development. Genes Dev. 13, 2538–2548 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jessen, K. R. et al. The Schwann cell precursor and its fate: a study of cell death and differentiation during gliogenesis in rat embryonic nerves. Neuron 12, 509–527 (1994). Here, the Schwann cell precursor is identified as a distinct intermediate in the generation of Schwann cells from neural crest cells.

    Article  CAS  PubMed  Google Scholar 

  9. Dong, Z. et al. NDF is a neuron–glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors. Neuron 15, 585–596 (1995). This study provides evidence that βNRG1 is an important neuron–glia signal that supports Schwann cell precursor survival and the progression of precursors to Schwann cells.

    Article  CAS  PubMed  Google Scholar 

  10. 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). A review that provides a comprehensive overview of the importance of neuregulin signalling in peripheral nerve development.

    Article  CAS  PubMed  Google Scholar 

  11. Joseph, N. M. et al. Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to Schwann cells. Development 131, 5599–5612 (2004). Using Cre-recombinase technology, this study provides evidence that DHH+ cells derived from embryonic mouse nerves give rise not only to Schwann cells but also to endoneurial fibroblasts.

    Article  CAS  PubMed  Google Scholar 

  12. Doetsch, F. The glial identity of neural stem cells. Nature Neurosci. 6, 1127–1134 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Gotz, M. Glial cells generate neurons — master control within CNS regions: developmental perspectives on neural stem cells. Neuroscientist 9, 379–397 (2003).

    Article  PubMed  CAS  Google Scholar 

  14. Bunge, R. P. Expanding roles for the Schwann cell: ensheathment, myelination trophism and regeneration. Curr. Opin. Neurobiol. 3, 805–809 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Jessen, K. R. & Mirsky, R. Schwann cells and their precursors emerge as major regulators of nerve development. Trends Neurosci. 22, 402–410 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Jessen, K. R. & Mirsky, R. Signals that determine Schwann cell identity. J. Anat. 200, 367–376 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Lobsiger, C. S., Taylor, V. & Suter, U. The early life of a Schwann cell. Biol. Chem. 383, 245–253 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Corfas, G., Velardez, M. O., Ko, C. P., Ratner, N. & Peles, E. Mechanisms and roles of axon–Schwann cell interactions. J. Neurosci. 24, 9250–9260 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sherman, D. & Brophy, P. Mechanisms of axon ensheathment and myelin growth. Nature Rev. Neurosci. 6, 683–690 (2005).

    Article  CAS  Google Scholar 

  21. Sherman, L., Stocker, K. M., Morrison, R. & Ciment, G. Basic fibroblast growth factor (bFGF) acts intracellularly to cause the transdifferentiation of avian neural crest-derived Schwann cell precursors into melanocytes. Development 118, 1313–1326 (1993).

    CAS  PubMed  Google Scholar 

  22. Hagedorn, L., Suter, U. & Sommer, L. P0 and PMP22 mark a multipotent neural crest-derived cell type that displays community effects in response to TGF-β family factors. Development 126, 3781–3794 (1999).

    CAS  PubMed  Google Scholar 

  23. Morrison, S. J., White, P. M., Zock, C. & Anderson, D. J. Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. Cell 96, 737–749 (1999). The authors show that cells isolated from peripheral nerves of embryonic rats self-renew, are multipotent in culture and on transplantation give rise to neurons and glia.

    Article  CAS  PubMed  Google Scholar 

  24. Scherer, S. S. & Salzer, J. in Glial Cell Development 2nd edn (eds Jessen, K. R. & Richardson, W. D.) 299–330 (Oxford Univ. Press, 2001).

    Google Scholar 

  25. Dupin, E., Real, C., Glavieux-Pardanaud, C., Vaigot, P. & Le Douarin, N. M. Reversal of developmental restrictions in neural crest lineages: transition from Schwann cells to glial-melanocytic precursors in vitro. Proc. Natl Acad. Sci. USA 100, 5229–5233 (2003). Shows that endothelin can induce Schwann cells derived from quail peripheral nerves to de-differentiate and give rise to both Schwann cells and melanocytes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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  PubMed  Google Scholar 

  27. Woodhoo, A., Dean, C. H., Droggiti, A., Mirsky, R. & Jessen, K. R. The trunk neural crest and its early glial derivatives: a study of survival responses, developmental schedules and autocrine mechanisms. Mol. Cell. Neurosci. 25, 30–41 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. White, P. M. et al. Neural crest stem cells undergo cell-intrinsic developmental changes in sensitivity to instructive differentiation signals. Neuron 29, 57–71 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. 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). When compared directly, migratory neural crest cells are less gliogenic than cells isolated from embryonic peripheral nerves. The transition is correlated with a marked increase in the ratio of Notch to Numb (a Notch inhibitor), which indicates how the sensitivity to Notch might be regulated during peripheral glial development.

    Article  CAS  PubMed  Google Scholar 

  30. 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 IGF, NT-3 and PDGF-BB. J. Neurosci. 19, 3847–3859 (1999). The authors show that Schwann cells acquire autocrine survival circuits that prevent cell death after deprivation of axonal contact, a survival mechanism that is crucial for axonal regrowth after injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shah, N. M., Marchionni, M. A., Isaacs, I., Stroobant, P. & Anderson, D. J. Glial growth factor restricts mammalian neural crest stem cells to a glial fate. Cell 77, 349–360 (1994). An early paper showing that neuregulin inhibits neuronal differentiation and permits glial differentiation in migrating neural crest cells.

    Article  CAS  PubMed  Google Scholar 

  32. Shah, N. M., Groves, A. K. & Anderson, D. J. Alternative neural crest cell fates are instructively promoted by TGFβ superfamily members. Cell 85, 331–343 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. 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). Shows that in vitro Notch inhibits neurogenesis and promotes gliogenesis in cells isolated from embryonic rat peripheral nerves.

    Article  CAS  PubMed  Google Scholar 

  34. Britsch, S. et al. The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev. 15, 66–78 (2001). Shows that SOX10 is required for the development of all peripheral glia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Paratore, C., Goerich, D. E., Suter, U., Wegner, M. & Sommer, L. Survival and glial fate acquisition of neural crest cells are regulated by an interplay between the transcription factor Sox10 and extrinsic combinatorial signalling. Development 128, 3949–3961 (2001).

    CAS  PubMed  Google Scholar 

  36. Britsch, S. et al. The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system. Genes Dev. 12, 1825–1836 (1998). Establishes a requirement for NRG1 and its receptors ErbB2 and ErbB3 in the migration of neural crest cells to regions where sympathetic ganglia form.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Morris, J. K. et al. Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development. Neuron 23, 273–283 (1999). Shows that mouse nerves deficient in ErbB2 receptors are deficient in SCPs and show aberrant motor and sensory neuron fasciculation and cell death.

    Article  CAS  PubMed  Google Scholar 

  38. 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). Demonstrates that neuregulin 1 type III isoforms are the crucial isoforms required for survival of SCPs, for axon fasciculation and for motor and sensory neuron survival in peripheral nerves.

    Article  CAS  PubMed  Google Scholar 

  39. Marchionni, M. A. et al. Glial growth factors are alternatively spliced ErbB2 ligands expressed in the nervous system. Nature 362, 312–318 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. 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 

  41. Longart, M., Liu, Y., Karavanova, I. & Buonanno, A. Neuregulin-2 is developmentally regulated and targeted to dendrites of central neurons. J. Comp. Neurol. 472, 156–172 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Michailov, G. V. et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 688–689 (2004). The authors provide in vivo evidence of a role for β NRG late in development, namely in regulating myelin sheath thickness.

    Article  CAS  Google Scholar 

  43. Winseck, A. K. et al. In vivo analysis of Schwann cell programmed cell death in the embryonic chick: regulation by axons and glial growth factor. J. Neurosci. 22, 4509–4521 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Grinspan, J. B., Marchionni, M. A., Reeves, M., Coulaloglou, M. & Scherer, S. S. Axonal interactions regulate Schwann cell apoptosis in developing peripheral nerve: neuregulin receptors and the role of neuregulins. J. Neurosci. 16, 6107–6118 (1996). Shows that Schwann cells in neonatal rat peripheral nerves are susceptible to apoptosis, which is increased by axotomy, and that exogenous neuregulin can rescue them from death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Trachtenberg, J. T. & Thompson, W. J. Schwann cell apoptosis at developing neuromuscular junctions is regulated by glial growth factor. Nature 379, 174–177 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Morrissey, T. K., Levi, A. D., Nuijens, A., Sliwkowski, M. X. & Bunge, R. P. Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2. Proc. Natl Acad. Sci. USA 92, 1431–1435 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lyons, D. A. et al. erbb3 and erbb2 are essential for Schwann cell migration and myelination in zebrafish. Curr. Biol. 15, 513–524 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Wang, S. & Barres, B. A. Up a Notch: instructing gliogenesis. Neuron 27, 197–200 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. 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  PubMed  Google Scholar 

  50. Schmid, R. S. et al. Neuregulin 1-erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex. Proc. Natl Acad. Sci. USA 100, 4251–4256 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schneider, C., Wicht, H., Enderich, J., Wegner, M. & Rohrer, H. Bone morphogenetic proteins are required in vivo for the generation of sympathetic neurons. Neuron 24, 861–870 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Dowsing, B. J. et al. Leukemia inhibitory factor is an autocrine survival factor for Schwann cells. J. Neurochem. 73, 96–104 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Weiner, J. A. & Chun, J. Schwann cell survival mediated by the signaling phospholipid lysophosphatidic acid. Proc. Natl Acad. Sci. USA 96, 5233–5238 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Stewart, H. J. S. et al. Developmental regulation and overexpression of the transcription factor AP-2, a potential regulator of the timing of Schwann cell generation. Eur. J. Neurosci. 14, 363–372 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Brennan, A. et al. Endothelins control the timing of Schwann cell generation in vitro and in vivo. Dev. Biol. 227, 545–557 (2000). Shows that endothelin slows down the progression of SCPs to Schwann cells, both in vivo and in vitro.

    Article  CAS  PubMed  Google Scholar 

  56. Murphy, P. et al. The regulation of Krox-20 expression reveals important steps in the control of peripheral glial cell development. Development 122, 2847–2857 (1996).

    CAS  PubMed  Google Scholar 

  57. Maro, G. S. et al. Neural crest boundary cap cells constitute a source of neuronal and glial cells of the PNS. Nature Neurosci. 7, 930–938 (2004). Shows that KROX20+ boundary cap cells situated at dorsal and ventral root entry and exit zones provide all the Schwann cells of the dorsal roots and most of those in the ventral roots, in addition to some nociceptive DRG neurons.

    Article  CAS  PubMed  Google Scholar 

  58. Bao, J., Wolpowitz, D., Role, L. W. & Talmage, D. A. Back signaling by the Nrg-1 intracellular domain. J. Cell Biol. 161, 1133–1141 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Vermeren, M. et al. Integrity of developing spinal motor columns is regulated by neural crest derivatives at motor exit points. Neuron 37, 403–415 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Grant, K. A., Raible, D. W. & Piotrowski, T. Regulation of latent sensory hair cell precursors by glia in the zebrafish lateral line. Neuron 45, 69–80 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Lopez-Schier, H. & Hudspeth, A. J. Supernumerary neuromasts in the posterior lateral line of zebrafish lacking peripheral glia. Proc. Natl Acad. Sci. USA 102, 1496–1501 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Alvarez-Buylla, A. & Lim, D. A. For the long run: maintaining germinal niches in the adult brain. Neuron 41, 683–686 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Gotz, M. & Barde, Y. -A. Defined and major intermediates between embryonic stem cells and CNS neurons. Neuron 46, 369–372 (2005).

    Article  PubMed  CAS  Google Scholar 

  64. Ciment, G. The melanocyte Schwann cell progenitor: a bipotent intermediate in the neural crest lineage. Comments Dev. Neurobiol. 1, 207–223 (1990).

    Google Scholar 

  65. Dupin, E., Glavieux, C., Vaigot, P. & Le Douarin, N. M. Endothelin 3 induces the reversion of melanocytes to glia through a neural crest-derived glial-melanocytic progenitor. Proc. Natl Acad. Sci. USA 97, 7882–7887 (2000). Shows that avian melanocytes can alter their differentiation programme in response to endothelin, leading them to generate both melanocytes and glia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rizvi, T. A. et al. A novel cytokine pathway suppresses glial cell melanogenesis after injury to adult nerve. J. Neurosci. 22, 9831–9840 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Le Douarin, N. M. & Kalcheim, C. The Neural Crest (Cambridge Univ. Press, Cambridge, 1999).

    Book  Google Scholar 

  68. Webster, H. de F. & Favilla, J. T. in Peripheral Neuropathy 2nd edn (eds Dyck, P. J., Thomas, P. K., Lambert, E. H. & Bunge, R. P.) 329 (W. B. Saunders, Philadelphia, 1984).

    Google Scholar 

  69. Xu, H., Wu, X. R., Wewer, U. M. & Engvall, E. Murine muscular dystrophy caused by a mutation in the laminin α2 (Lama2) gene. Nature Genet. 8, 297–302 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. Feltri, M. L. et al. Conditional disruption of β 1 integrin in Schwann cells impedes interactions with axons. J. Cell Biol. 156, 199–209 (2002). The authors show that conditional ablation of β 1 integrin in developing Schwann cells causes severe defects in the process by which Schwann cells and axons segregate prior to myelination, although proliferation and cell death are unaffected.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Darbas, A. et al. Cell autonomy of the mouse claw paw mutation. Dev. Biol. 272, 470–482 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Pietri, T. et al. Conditional β1-integrin deletion in neural crest cells causes severe developmental alterations of the peripheral nervous system. Development 131, 3871–3883 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Yang, D. et al. Coordinate control of axon defasciculation and myelination by laminin-2 and -8. J. Cell Biol. 168, 655–666 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yu, W. -M., Feltri, M. L., Wrabetz, L., Strickland, S. & Chen, Z. -L. Schwann cell-specific ablation of laminin γ1 causes apoptosis and prevents proliferation. J. Neurosci. 25, 4463–4472 (2005). Shows that depletion of all laminin isoforms in Schwann cells results in failure to extend processes and defective axonal sorting prior to myelination, which leads to large scale arrest at the promyelinating stage. Furthermore, lack of laminin results in decreased proliferation and increased apoptosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cheng, H. L., Steinway, M., Delaney, C. L., Franke, T. F. & Feldman, E. L. IGF-I promotes Schwann cell motility and survival via activation of Akt. Mol. Cell. Endocrinol. 170, 211–215 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Meintanis, S., Thomaidou, D., Jessen, K. R., Mirsky, R. & Matsas, R. The neuron–glia signal β-neuregulin promotes Schwann cell motility via the MAPK pathway. Glia 34, 39–51 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Yamauchi, J., Chan, J. R. & Shooter, E. M. Neurotrophins regulate Schwann cell migration by activating divergent signalling pathways dependent on Rho GTPases. Proc. Natl Acad. Sci. USA 101, 8774–8779 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Fragoso, G. et al. Inhibition of p38 mitogen-activated protein kinase interferes with cell shape changes and gene expression associated with Schwann cell myelination. Exp. Neurol. 183, 34–46 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Salzer, J. L., Williams, A. K., Glaser, L. & Bunge, R. P. Studies of Schwann cell proliferation. II. Characterization of the stimulation and specificity of the response to a neurite membrane fraction. J. Cell Biol. 84, 753–766 (1980).

    Article  CAS  PubMed  Google Scholar 

  80. Komiyama, A. & Suzuki, K. Age-related differences in proliferative responses of Schwann cells during Wallerian degeneration. Brain Res. 573, 267–275 (1992).

    Article  CAS  PubMed  Google Scholar 

  81. Syroid, D. E. et al. Induction of postnatal Schwann cell death by the low-affinity neurotrophin receptor in vitro and after axotomy. J. Neurosci. 20, 5741–5747 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Parkinson, D. B. et al. Transforming growth factor β (TGFβ) mediates Schwann cell death in vitro and in vivo: examination of c-Jun activation, interactions with survival signals, and the relationship of TGFβ mediated death to Schwann cell differentiation. J. Neurosci. 21, 8572–8585 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Parkinson, D. B. et al. Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death. J. Cell Biol. 164, 385–394 (2004). Shows that KROX20 inactivates Schwann cell proliferation in response to NRG1 and prevents cell death in response to TGFβ through inhibition of the JNK pathway. KROX20 also induces the expression of myelin genes in unrelated fibroblastic cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Parkinson, D. B., Bhaskaran, A., Mirsky, R. & Jessen, K. R. Regulation of the myelinating phenotype of Schwann cells by Krox-20. Medimond International Proceedings, VII European Meeting on Glial Cell Function in Health and Disease, Amsterdam 139–143 (2005).

  85. Kioussi, C., Gross, M. K. & Gruss, P. Pax3: a paired domain gene as a regulator in PNS myelination. Neuron 15, 553–562 (1995).

    Article  CAS  PubMed  Google Scholar 

  86. Le, N. et al. Analysis of congenital hypomyelinating Egr2Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination. Proc. Natl Acad. Sci. USA 102, 2596–2601 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Fields, R. D. & Stevens, B. ATP: an extracellular signalling molecule between neurones and glia. Trends Neurosci. 23, 625–633 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Maurel, P. & Salzer, J. L. Axonal regulation of Schwann cell proliferation and survival and the initial events of myelination requires PI3-kinase activity. J. Neurosci. 20, 4635–4645 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wegner, M. Transcriptional control in myelinating glia: the basic recipe. Glia 29, 118–123 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Wegner, M. Transcriptional control in myelinating glia: flavors and spices. Glia 31, 1–14 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Topilko, P. & Meijer, D. in Glial Cell Development (eds Jessen, K. R. & Richardson, W. D.) 223–244 (Oxford Univ. Press, 2001).

    Google Scholar 

  92. 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). Shows that in addition to the requirement for transcription factor OCT6 in controlling peripheral myelination, the related factor BRN2 also has a role.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Atanasoski, S. et al. The protooncogene Ski controls Schwann cell proliferation and myelination. Neuron 43, 499–511 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Jessen, K. R. Glial cells. Int. J. Biochem. Cell Biol. 36, 1861–1867 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Falls, D. Neuregulins: functions, forms and signaling strategies. Exp. Cell Res. 284, 14–30 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Buonanno, A. & Fischbach, G. D. Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr. Opin. Neurobiol. 11, 287–296 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Archelos, J. J. et al. Production and characterization of monoclonal antibodies to the extracellular domain of P0. J. Neurosci. Res. 35, 46–53 (1993).

    Article  CAS  PubMed  Google Scholar 

  98. Jessen, K. R. & Mirsky, R. in Neuroglia 2nd edn (eds Kettenmann, H. & Ransom, B.) 85–100 (Oxford Univ. Press, 2005).

    Google Scholar 

  99. Mirsky, R. & Jessen, K. R. in Peripheral Neuropathy (eds Dyck, P. J. & Thomas, P. K.) 341–376 (Elsevier, USA, 2005).

    Book  Google Scholar 

  100. Dong, Z. et al. Schwann cell development in embryonic mouse nerves. J. Neurosci. Res. 56, 334–348 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. Leimeroth, R. et al. Membrane-bound neuregulin1 type III actively promotes Schwann cell differentiation of multipotent progenitor cells. Dev. Biol. 246, 245–258 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Syroid, D. E. et al. Cell death in the Schwann cell lineage and its regulation by neuregulin. Proc. Natl Acad. Sci. USA 93, 9229–9234 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Parkinson, D. B., Langner, K., Sharghi-Namini, S., Jessen, K. R. & Mirsky, R. β-neuregulin and autocrine mediated survival of Schwann cells requires activity of Ets family transcription factors. Mol. Cell. Neurosci. 20, 154–167 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Eccleston, P. A. Regulation of Schwann cell proliferation: mechanisms involved in peripheral nerve development. Exp. Cell Res. 199, 1–9 (1992).

    Article  CAS  PubMed  Google Scholar 

  105. Koenig, H. L. et al. Progesterone synthesis and myelin formation by Schwann cells. Science 268, 1500–1503 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Stewart, H. J. S. et al. Regulation of rat Schwann cell P0 expression and DNA synthesis by insulin-like growth factors in vitro. Eur. J. Neurosci. 8, 553–564 (1996).

    Article  CAS  PubMed  Google Scholar 

  107. Chan, J. R., Cosgaya, J. M., Wu, Y. J. & Shooter, E. M. Neurotrophins are key mediators of the myelination program in the peripheral nervous system. Proc. Natl Acad. Sci. USA 98, 14661–14668 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Höke, A. et al. Glial cell line-derived neurotrophic factor alters axon Schwann cell units and promotes myelination in unmyelinated nerve fibers. J. Neurosci. 23, 561–567 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Stevens, B., Ishibashi, T., Chen, J. -F. & Fields, R. D. Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells. Neuron Glia Biol. 1, 23–34 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Einheber, S., Hannocks, M. -J., Metz, C. N., Rifkin, D. B. & Salzer, J. L. Transforming growth factor-β 1 regulates axon–Schwann cell interactions. J. Cell Biol. 129, 443–458 (1995).

    Article  CAS  PubMed  Google Scholar 

  111. Guenard, V. et al. Effect of transforming growth factor-β 1 and -β 2 on Schwann cell proliferation on neurites. Glia 13, 309–318 (1995).

    Article  CAS  PubMed  Google Scholar 

  112. 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 

  113. Takahashi, M. & Osumi, N. Identification of a novel type II classical cadherin: rat cadherin19 is expressed in the cranial ganglia and Schwann cell precursors during development. Dev. Dyn. 232, 200–208 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Bitgood, M. J. & McMahon, A. P. Hedgehog and Bmp genes are co-expressed at many diverse sites of cell–cell interaction in the mouse embryo. Dev. Biol. 172, 126–138 (1995).

    Article  CAS  PubMed  Google Scholar 

  115. Parmantier, E. et al. Schwann cell-derived Desert Hedgehog controls the development of peripheral nerve sheaths. Neuron 23, 713–724 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Blanchard, A. D. et al. Oct-6 (SCIP/Tst-1) is expressed in Schwann cell precursors, embryonic Schwann cells, and postnatal myelinating Schwann cells: comparison with Oct-1, Krox-20, and Pax-3. J. Neurosci. Res. 46, 630–640 (1996).

    Article  CAS  PubMed  Google Scholar 

  117. Griffiths, I. et al. Current concepts of PLP and its role in the nervous system. Microsc. Res. Tech. 41, 344–358 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Lee, M. et al. P0 is constitutively expressed in the rat neural crest and embryonic nerves and is negatively and positively regulated by axons to generate non-myelin-forming and myelin-forming Schwann cells, respectively. Mol. Cell. Neurosci. 8, 336–350 (1997).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Kristjan R. Jessen.

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DATABASES

Entrez Gene

BMP2

BRN2

DHH

Egr2

GFAP

IGF2

LIF

NRG1

OCT6

Pax6

PDGFB

SOX10

FURTHER INFORMATION

Jessen and Mirsky's laboratory

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Jessen, K., Mirsky, R. The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci 6, 671–682 (2005). https://doi.org/10.1038/nrn1746

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