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Journal of Clinical Immunology
Published in: Journal of Clinical Immunology 1/2013

01-01-2013

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

Authors: André Heinen, Helmar C. Lehmann, Patrick Küry

Published in: Journal of Clinical Immunology | Special Issue 1/2013

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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.
Literature
1.
Son YJ, Thompson WJ. Schwann cell processes guide regeneration of peripheral axons. Neuron. 1995;14(1):125–32.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
4.
Jessen KR, Mirsky R. Negative regulation of myelination: relevance for development, injury, and demyelinating disease. Glia. 2008;56(14):1552–65.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
18.
Kioussi C, Gross MK, Gruss P. Pax3: a paired domain gene as a regulator in PNS myelination. Neuron. 1995;15(3):553–62.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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
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.PubMedCrossRef
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.PubMedCrossRef
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
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.PubMedCrossRef
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.PubMedCrossRef
38.
Kondo T, Raff M. Basic helix-loop-helix proteins and the timing of oligodendrocyte differentiation. Development. 2000;127(14):2989–98.PubMed
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
Metadata
Title
Negative Regulators of Schwann Cell Differentiation—Novel Targets for Peripheral Nerve Therapies?
Authors
André Heinen
Helmar C. Lehmann
Patrick Küry
Publication date
01-01-2013
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue Special Issue 1/2013
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-012-9786-9

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