Skip to main content

Advertisement

Log in

Negative Regulators of Schwann Cell Differentiation—Novel Targets for Peripheral Nerve Therapies?

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

As myelinating glial cells of the peripheral nervous system, Schwann cells wrap around axons and thereby provide insulation, acceleration of electric signal propagation, and axonal protection and maintenance. Schwann cells are main effectors for regeneration in a variety of peripheral neuropathic conditions, including inherited, inflammatory, toxic, and diabetic neuropathies, as well as traumatic injuries to peripheral nerve fibers. Due to their high differentiation plasticity, these cells can respond to injury and disease by myelin sheath degradation, dedifferentiation into an immature Schwann cell-like phenotype, proliferation, and remyelination of sprouting axons. In doing so, they can support and promote axonal regrowth and target tissue innervation. Developmental differentiation as well as regenerative de- and redifferentiation are tightly controlled by a balance of positive and negative regulators of Schwann cell maturation. Since misregulated expression of such negative regulators is potentially involved in inefficient or failed regeneration, we will provide an overview about recent work revealing the complex interactions between extrinsic and intrinsic signals in the inhibition of Schwann cell differentiation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Son YJ, Thompson WJ. Schwann cell processes guide regeneration of peripheral axons. Neuron. 1995;14(1):125–32.

    Article  PubMed  CAS  Google Scholar 

  2. Martini R, Fischer S, López-Vales R, David S. Interactions between Schwann cells and macrophages in injury and inherited demyelinating disease. Glia. 2008;56(14):1566–77.

    Article  PubMed  Google Scholar 

  3. Hoke A. Mechanisms of disease: what factors limit the success of peripheral nerve regeneration in humans? Nat Clin Pract Neurol. 2006;2(8):448–54.

    Article  PubMed  CAS  Google Scholar 

  4. Jessen KR, Mirsky R. Negative regulation of myelination: relevance for development, injury, and demyelinating disease. Glia. 2008;56(14):1552–65.

    Article  PubMed  Google Scholar 

  5. Michailov GV, Sereda MW, Brinkmann BG, Fischer TM, Haug B, Birchmeier C, Role L, Lai C, Schwab MH, Nave KA. Axonal neuregulin-1 regulates myelin sheath thickness. Science. 2004;304(5671):700–3.

    Article  PubMed  CAS  Google Scholar 

  6. Nagarajan R, Svaren J, Le N, Araki T, Watson M, Milbrandt J. EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression. Neuron. 2001;30(2):355–68.

    Article  PubMed  CAS  Google Scholar 

  7. Decker L, Desmarquet-Trin-Dinh C, Taillebourg E, Ghislain J, Vallat JM, Charnay P. Peripheral myelin maintenance is a dynamic process requiring constant Krox20 expression. J Neurosci. 2006;26(38):9771–9.

    Article  PubMed  CAS  Google Scholar 

  8. Britsch S, Goerich DE, Riethmacher D, Peirano RI, Rossner M, Nave KA, Birchmeier C, Wegner M. The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev. 2001;15(1):66–78.

    Article  PubMed  CAS  Google Scholar 

  9. Bremer M, Fröb F, Kichko T, Reeh P, Tamm ER, Suter U, Wegner M. Sox10 is required for Schwann-cell homeostasis and myelin maintenance in the adult peripheral nerve. Glia. 2011;59(7):1022–32. doi:10.1002/glia.21173.

    Article  PubMed  Google Scholar 

  10. Jaegle M, Mandemakers W, Broos L, Zwart R, Karis A, Visser P, Grosveld F, Meijer D. The POU factor Oct-6 and Schwann cell differentiation. Science. 1996;273(5274):507–10.

    Article  PubMed  CAS  Google Scholar 

  11. Nickols JC, Valentine W, Kanwal S, Carter BD. Activation of the transcription factor NF-kappaB in Schwann cells is required for peripheral myelin formation. Nat Neurosci. 2003;6(2):161–7.

    Article  PubMed  CAS  Google Scholar 

  12. Parkinson DB, Bhaskaran A, Arthur-Farraj P, Noon LA, Woodhoo A, Lloyd AC, Feltri ML, Wrabetz L, Behrens A, Mirsky R, Jessen KR. c-Jun is a negative regulator of myelination. J Cell Biol. 2008;181(4):625–37.

    Article  PubMed  CAS  Google Scholar 

  13. Woodhoo A, Alonso MB, Droggiti A, Turmaine M, D'Antonio M, Parkinson DB, Wilton DK, Al-Shawi R, Simons P, Shen J, Guillemot F, Radtke F, Meijer D, Feltri ML, Wrabetz L, Mirsky R, Jessen KR. Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat Neurosci. 2009;12(7):839–47.

    Article  PubMed  CAS  Google Scholar 

  14. Le N, Nagarajan R, Wang JY, Araki T, Schmidt RE, Milbrandt J. Analysis of congenital hypomyelinating Egr2Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination. Proc Natl Acad Sci U S A. 2005;102(7):2596–601.

    Article  PubMed  CAS  Google Scholar 

  15. Hutton EJ, Carty L, Laurá M, Houlden H, Lunn MP, Brandner S, Mirsky R, Jessen K, Reilly MM. c-Jun expression in human neuropathies: a pilot study. J Peripher Nerv Syst. 2011;16(4):295–303.

    Article  PubMed  Google Scholar 

  16. Fontana X, Hristova M, Da Costa C, Patodia S, Thei L, Makwana M, Spencer-Dene B, Latouche M, Mirsky R, Jessen KR, Klein R, Raivich G, Behrens A. c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling. J Cell Biol. 2012;198(1):127–41.

    Article  PubMed  CAS  Google Scholar 

  17. Mager GM, Ward RM, Srinivasan R, Jang SW, Wrabetz L, Svaren J. Active gene repression by the Egr2.NAB complex during peripheral nerve myelination. J Biol Chem. 2008;283(26):18187–97.

    Article  PubMed  CAS  Google Scholar 

  18. Kioussi C, Gross MK, Gruss P. Pax3: a paired domain gene as a regulator in PNS myelination. Neuron. 1995;15(3):553–62.

    Article  PubMed  CAS  Google Scholar 

  19. Doddrell RD, Dun XP, Moate RM, Jessen KR, Mirsky R, Parkinson DB. Regulation of Schwann cell differentiation and proliferation by the Pax-3 transcription factor. Glia. 2012;60(9):1269–78.

    Article  PubMed  Google Scholar 

  20. Topilko P, Levi G, Merlo G, Mantero S, Desmarquet C, Mancardi G, Charnay P. Differential regulation of the zinc finger genes Krox-20 and Krox-24 (Egr-1) suggests antagonistic roles in Schwann cells. J Neurosci Res. 1997;50(5):702–12.

    Article  PubMed  CAS  Google Scholar 

  21. Levy D, Kubes P, Zochodne DW. Delayed peripheral nerve degeneration, regeneration, and pain in mice lacking inducible nitric oxide synthase. J Neuropathol Exp Neurol. 2001;60(5):411–21.

    PubMed  CAS  Google Scholar 

  22. Lee H, Park C, Cho IH, Kim HY, Jo EK, Lee S, Kho HS, Choi SY, Oh SB, Park K, Kim JS, Lee SJ. Double-stranded RNA induces iNOS gene expression in Schwann cells, sensory neuronal death, and peripheral nerve demyelination. Glia. 2007;55(7):712–22.

    Article  PubMed  Google Scholar 

  23. Harrisingh MC, Perez-Nadales E, Parkinson DB, Malcolm DS, Mudge AW, Lloyd AC. The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation. EMBO J. 2004;23(15):3061–71. Epub 2004 Jul 8.

    Article  PubMed  CAS  Google Scholar 

  24. Ogata T, Iijima S, Hoshikawa S, Miura T, Yamamoto S, Oda H, Nakamura K, Tanaka S. Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination. J Neurosci. 2004;24(30):6724–32.

    Article  PubMed  CAS  Google Scholar 

  25. Napoli I, Noon LA, Ribeiro S, Kerai AP, Parrinello S, Rosenberg LH, Collins MJ, Harrisingh MC, White IJ, Woodhoo A, Lloyd AC. A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron. 2012;73(4):729–42.

    Article  PubMed  CAS  Google Scholar 

  26. Zhang P, Liégeois NJ, Wong C, Finegold M, Hou H, Thompson JC, Silverman A, Harper JW, DePinho RA, Elledge SJ. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature. 1997;387(6629):151–8.

    Article  PubMed  CAS  Google Scholar 

  27. Yan Y, Frisén J, Lee MH, Massagué J, Barbacid M. Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development. Genes Dev. 1997;11(8):973–83.

    Article  PubMed  CAS  Google Scholar 

  28. Yokoo T, Toyoshima H, Miura M, Wang Y, Iida KT, Suzuki H, Sone H, Shimano H, Gotoda T, Nishimori S, Tanaka K, Yamada N. p57Kip2 regulates actin dynamics by binding and translocating LIM-kinase 1 to the nucleus. J Biol Chem. 2003;278(52):52919–23.

    Article  PubMed  CAS  Google Scholar 

  29. Heinen A, Kremer D, Göttle P, Kruse F, Hasse B, Lehmann H, Hartung HP, Küry P. The cyclin-dependent kinase inhibitor p57kip2 is a negative regulator of Schwann cell differentiation and in vitro myelination. Proc Natl Acad Sci U S A. 2008;105(25):8748–53.

    Article  PubMed  CAS  Google Scholar 

  30. Kremer D, Heinen A, Jadasz J, Göttle P, Zimmermann K, Zickler P, Jander S, Hartung HP, Küry P. p57kip2 is dynamically regulated in experimental autoimmune encephalomyelitis and interferes with oligodendroglial maturation. Proc Natl Acad Sci U S A. 2009;106(22):9087–92.

    Article  PubMed  CAS  Google Scholar 

  31. Heinen A, Tzekova N, Graffmann N, Torres KJ, Uhrberg M, Hartung HP, Küry P. Histone methyltransferase enhancer of zeste homolog 2 regulates Schwann cell differentiation. Glia. 2012 Jul 20;doi: 10.1002/glia.22388. [Epub ahead of print]

  32. Küry P, Greiner-Petter R, Cornely C, Jürgens T, Müller HW. Mammalian achaete scute homolog 2 is expressed in the adult sciatic nerve and regulates the expression of Krox24, Mob-1, CXCR4, and p57kip2 in Schwann cells. J Neurosci. 2002;22(17):7586–95.

    PubMed  Google Scholar 

  33. Atanasoski S, Boller D, De Ventura L, Koegel H, Boentert M, Young P, Werner S, Suter U. Cell cycle inhibitors p21 and p16 are required for the regulation of Schwann cell proliferation. Glia. 2006;53(2):147–57.

    Article  PubMed  Google Scholar 

  34. Iacovelli J, Lopera J, Bott M, Baldwin E, Khaled A, Uddin N, Fernandez-Valle C. Serum and forskolin cooperate to promote G1 progression in Schwann cells by differentially regulating cyclin D1, cyclin E1, and p27Kip expression. Glia. 2007;55(16):1638–47.

    Article  PubMed  Google Scholar 

  35. Fernandez-Valle C, Gorman D, Gomez AM, Bunge MB. Actin plays a role in both changes in cell shape and gene-expression associated with Schwann cell myelination. J Neurosci. 1997;17(1):241–50.

    PubMed  CAS  Google Scholar 

  36. Melendez-Vasquez CV, Einheber S, Salzer JL. Rho kinase regulates schwann cell myelination and formation of associated axonal domains. J Neurosci. 2004;24(16):3953–63.

    Article  PubMed  CAS  Google Scholar 

  37. Heinen A, Kremer D, Hartung HP, Küry P. p57 kip2's role beyond Schwann cell cycle control. Cell Cycle. 2008;7(18):2781–6.

    Article  PubMed  CAS  Google Scholar 

  38. Kondo T, Raff M. Basic helix-loop-helix proteins and the timing of oligodendrocyte differentiation. Development. 2000;127(14):2989–98.

    PubMed  CAS  Google Scholar 

  39. Liu A, Li J, Marin-Husstege M, Kageyama R, Fan Y, Gelinas C, Casaccia-Bonnefil P. A molecular insight of Hes5-dependent inhibition of myelin gene expression: old partners and new players. EMBO J. 2006;25(20):4833–42.

    Article  PubMed  CAS  Google Scholar 

  40. Cotter L, Ozçelik M, Jacob C, Pereira JA, Locher V, Baumann R, Relvas JB, Suter U, Tricaud N. Dlg1-PTEN interaction regulates myelin thickness to prevent damaging peripheral nerve overmyelination. Science. 2010;328(5984):1415–8.

    Article  PubMed  CAS  Google Scholar 

  41. Goebbels S, Oltrogge JH, Wolfer S, Wieser GL, Nientiedt T, Pieper A, Ruhwedel T, Groszer M, Sereda MW, Nave KA. Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy. EMBO Mol Med. 2012;4(6):486–99.

    Article  PubMed  CAS  Google Scholar 

  42. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006;314(5799):664–6. Epub 2006 Sep 21.

    Article  PubMed  CAS  Google Scholar 

  43. Hu X, He W, Diaconu C, Tang X, Kidd GJ, Macklin WB, Trapp BD, Yan R. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB J. 2008;22(8):2970–80. Epub 2008 Apr 15.

    Article  PubMed  CAS  Google Scholar 

  44. La Marca R, Cerri F, Horiuchi K, Bachi A, Feltri ML, Wrabetz L, Blobel CP, Quattrini A, Salzer JL, Taveggia C. TACE (ADAM17) inhibits Schwann cell myelination. Nat Neurosci. 2011;14(7):857–65.

    Article  PubMed  Google Scholar 

  45. Yamauchi J, Miyamoto Y, Chan JR, Tanoue A. ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration. J Cell Biol. 2008;181(2):351–65.

    Article  PubMed  CAS  Google Scholar 

  46. Yamauchi J, Miyamoto Y, Hamasaki H, Sanbe A, Kusakawa S, Nakamura A, Tsumura H, Maeda M, Nemoto N, Kawahara K, Torii T, Tanoue A. The atypical Guanine-nucleotide exchange factor, dock7, negatively regulates schwann cell differentiation and myelination. J Neurosci. 2011;31(35):12579–92.

    Article  PubMed  CAS  Google Scholar 

  47. Makoukji J, Shackleford G, Meffre D, Grenier J, Liere P, Lobaccaro JM, Schumacher M, Massaad C. Interplay between LXR and Wnt/β-catenin signaling in the negative regulation of peripheral myelin genes by oxysterols. J Neurosci. 2011;31(26):9620–9.

    Article  PubMed  CAS  Google Scholar 

  48. Tawk M, Makoukji J, Belle M, Fonte C, Trousson A, Hawkins T, Li H, Ghandour S, Schumacher M, Massaad C. Wnt/beta-catenin signaling is an essential and direct driver of myelin gene expression and myelinogenesis. J Neurosci. 2011;31(10):3729–42.

    Article  PubMed  CAS  Google Scholar 

  49. Saher G, Quintes S, Möbius W, Wehr MC, Krämer-Albers EM, Brügger B, Nave KA. Cholesterol regulates the endoplasmic reticulum exit of the major membrane protein P0 required for peripheral myelin compaction. J Neurosci. 2009;29(19):6094–104.

    Article  PubMed  CAS  Google Scholar 

  50. Ji Y, Tao T, Cheng C, Yang H, Wang Y, Yang J, Liu H, He X, Wang H, Shen A. SSeCKS is a suppressor in Schwann cell differentiation and myelination. Neurochem Res. 2010;35(2):219–26.

    Article  PubMed  CAS  Google Scholar 

  51. Nauert JB, Klauck TM, Langeberg LK, Scott JD. Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein. Curr Biol. 1997;7(1):52–62.

    Article  PubMed  CAS  Google Scholar 

  52. Howe DG, McCarthy KD. Retroviral inhibition of cAMP-dependent protein kinase inhibits myelination but not Schwann cell mitosis stimulated by interaction with neurons. J Neurosci. 2000;20(10):3513–21.

    PubMed  CAS  Google Scholar 

  53. Atanasoski S, Scherer SS, Sirkowski E, Leone D, Garratt AN, Birchmeier C, Suter U. ErbB2 signaling in Schwann cells is mostly dispensable for maintenance of myelinated peripheral nerves and proliferation of adult Schwann cells after injury. J Neurosci. 2006;26(7):2124–31.

    Article  PubMed  CAS  Google Scholar 

  54. Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A, Krezel W, Kagechika H, Bauer J, Zhao C, Evercooren AB, Chambon P, Ffrench-Constant C, Franklin RJ. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci. 2011;14(1):45–53.

    Article  PubMed  CAS  Google Scholar 

  55. Zhelyaznik N, Schrage K, McCaffery P, Mey J. Activation of retinoic acid signalling after sciatic nerve injury: up-regulation of cellular retinoid binding proteins. Eur J Neurosci. 2003;18(5):1033–40.

    Article  PubMed  Google Scholar 

  56. Latasa MJ, Ituero M, Moran-Gonzalez A, Aranda A, Cosgaya JM. Retinoic acid regulates myelin formation in the peripheral nervous system. Glia. 2010;58(12):1451–64.

    PubMed  Google Scholar 

  57. Zhelyaznik N, Mey J. Regulation of retinoic acid receptors alpha, beta and retinoid X receptor alpha after sciatic nerve injury. Neuroscience. 2006;141(4):1761–74.

    Article  PubMed  CAS  Google Scholar 

  58. Arrieta O, García-Navarrete R, Zúñiga S, Ordóñez G, Ortiz A, Palencia G, Morales-Espinosa D, Hernández-Pedro N, Sotelo J. Retinoic acid increases tissue and plasma contents of nerve growth factor and prevents neuropathy in diabetic mice. Eur J Clin Invest. 2005;35(3):201–7.

    Article  PubMed  CAS  Google Scholar 

  59. Arrieta O, Hernández-Pedro N, Fernández-González-Aragón MC, Saavedra-Pérez D, Campos-Parra AD, Ríos-Trejo MÁ, Cerón-Lizárraga T, Martínez-Barrera L, Pineda B, Ordóñez G, Ortiz-Plata A, Granados-Soto V, Sotelo J. Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer. Neurology. 2011;77(10):987–95.

    Article  PubMed  CAS  Google Scholar 

  60. Limpert AS, Carter BD. Axonal neuregulin 1 type III activates NF-kappaB in Schwann cells during myelin formation. J Biol Chem. 2010;285(22):16614–22.

    Article  PubMed  CAS  Google Scholar 

  61. Morton PD, Johnstone JT, Ramos AY, Liebl DJ, Bunge MB, Bethea JR. Nuclear factor-κB activation in Schwann cells regulates regeneration and remyelination. Glia. 2012;60(4):639–50.

    Article  PubMed  Google Scholar 

  62. Chen Y, Wang H, Yoon SO, Xu X, Hottiger MO, Svaren J, Nave KA, Kim HA, Olson EN, Lu QR. HDAC-mediated deacetylation of NF-κB is critical for Schwann cell myelination. Nat Neurosci. 2011;14(4):437–41.

    Article  PubMed  CAS  Google Scholar 

  63. Berti-Mattera LN, Larkin B, Hourmouzis Z, Kern TS, Siegel RE. NF-κB subunits are differentially distributed in cells of lumbar dorsal root ganglia in naïve and diabetic rats. Neurosci Lett. 2011;490(1):41–5.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Patrick Küry.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heinen, A., Lehmann, H.C. & Küry, P. Negative Regulators of Schwann Cell Differentiation—Novel Targets for Peripheral Nerve Therapies?. J Clin Immunol 33 (Suppl 1), 18–26 (2013). https://doi.org/10.1007/s10875-012-9786-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-012-9786-9

Keywords

Navigation