Biology of Peripheral Inherited Neuropathies: Schwann Cell Axonal Interactions

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 652)


Development and maintenance of PNS myelin depends on continual signaling from axons ensheathed by myelin. Recent advances have demonstrated the roles of neuregulin 1 type III, Erb2/3 and intracellular signal transduction pathways in inducing Schwann cell myelination. Alternatively, maintenance of myelinated axons depends on healthy myelinating Schwann cells. Axonal degeneration is a feature of virtually all inherited demyelinating neuropathies and in many cases is more responsible for clinical impairment than the primary demyelination. Signaling mechanisms through which demyelinating Schwann cells damage axons are not well understood. In this review several examples of potential mechanisms by which demyelinating neuropathies damage axons will be presented. Understanding the molecular basis of Schwann cell-axonal interactions will not only increase the understanding of PNS biology but also identify therapeutic targets for inherited neuropathies.


Myelin PNS Schwann cell Axon Genetic Neuropathy 


  1. 1.
    Charcot J, Marie P. Sue une forme particulaire d’atrophie musculaire progressive souvent familial debutant par les pieds et les jamber et atteingnant plus tard les mains. Re Med 1886;6:97–138.Google Scholar
  2. 2.
    Tooth H. The peroneal type of progressive muscular atrophy. London: Lewis, 1886.Google Scholar
  3. 3.
    Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin Genet 1974;6:98–118.CrossRefPubMedGoogle Scholar
  4. 4.
    Harrison RG. Neuroblast versus sheath cell in the development of peripheral nerves. J Comp Neurol 1924;37: 123–245.CrossRefGoogle Scholar
  5. 5.
    Le Douarin NM, Dupin E. Cell lineage analysis in neural crest ontogeny. J Neurobiol 1993;24:146–161.CrossRefPubMedGoogle Scholar
  6. 6.
    Webster, H, De F. Development of peripheral nerve fibres. In: Peripheral Neuropathy In: P.J. Dyck, P.K. Thomas, J.W. Griffin, P.A. Low, and J.F. Poduslo, eds. 3rd ed. Philadelphia: W. B. Saunders, 1993: 243–266.Google Scholar
  7. 7.
    Scherer SS. The biology and pathobiology of Schwann cells. Curr Opin Neurol 1997;10:386–397.CrossRefPubMedGoogle Scholar
  8. 8.
    Mirsky R, Jessen KR. Schwann cell development, differentiation and myelination. Curr Opin Neurobiol 1996;6:89–96.CrossRefPubMedGoogle Scholar
  9. 9.
    Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003;284:14–30.CrossRefPubMedGoogle Scholar
  10. 10.
    Meyer D, Yamaai T, Garratt A, et al. Isoform-specific expression and function of neuregulin. Development 1997;124:3575–3586.PubMedGoogle Scholar
  11. 11.
    Wang JY, Miller SJ, Falls DL. The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain. J Biol Chem 2001;276:2841–2851.CrossRefPubMedGoogle Scholar
  12. 12.
    Citri A, Skaria KB, Yarden Y. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res 2003;284:54–65.CrossRefPubMedGoogle Scholar
  13. 13.
    Nave KA, Salzer JL. Axonal regulation of myelination by neuregulin 1. Curr Opin Neurobiol 2006;16:492–500.CrossRefPubMedGoogle Scholar
  14. 14.
    Taveggia C, Zanazzi G, Petrylak A, et al. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 2005;47:681–694.CrossRefPubMedGoogle Scholar
  15. 15.
    Michailov GV, Sereda MW, Brinkmann BG, et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 2004;304:700–703.CrossRefPubMedGoogle Scholar
  16. 16.
    Shy ME. Therapeutic strategies for the inherited neuropathies. Neuromolecular Med 2006;8:255–278.CrossRefPubMedGoogle Scholar
  17. 17.
    Warner LE, Mancias P, Butler IJ, et al. Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet 1998;18:382–384.CrossRefPubMedGoogle Scholar
  18. 18.
    Inoue K, Shilo K, Boerkoel CF, et al. Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation. Ann Neurol 2002;52:836–842.CrossRefPubMedGoogle Scholar
  19. 19.
    Arroyo EJ, Scherer SS. On the molecular architecture of myelinated fibers. Histochem Cell Biol 2000;113:1–18.CrossRefPubMedGoogle Scholar
  20. 20.
    Salzer JL. Polarized domains of myelinated axons. Neuron 2003;40:297–318.CrossRefPubMedGoogle Scholar
  21. 21.
    Lupski JR, de Oca-Luna RM, Slaugenhaupt S, et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 1991;66:219–232.CrossRefPubMedGoogle Scholar
  22. 22.
    Raeymaekers P, Timmerman V, Nelis E, et al. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscul Disord 1991;1:93–97.CrossRefPubMedGoogle Scholar
  23. 23.
    Lupski JR, de Oca-Luna RM, Slaugenhaupt S, et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 1991;66:219–232.CrossRefPubMedGoogle Scholar
  24. 24.
    Magyar JP, Martini R, Ruelicke T, et al. Impaired differentiation of Schwann cells in transgenic mice with increased PMP22 gene dosage. J Neurosci 1996;16: 5351–5360.PubMedGoogle Scholar
  25. 25.
    Sereda M, Griffiths I, Puhlhofer A, et al. A transgenic rat model of Charcot-Marie-Tooth disease. Neuron 1996;16:1049–1060.CrossRefPubMedGoogle Scholar
  26. 26.
    Huxley C, Passage E, Manson A, et al. Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA. Hum Mol Genet 1996;5:563–569.CrossRefPubMedGoogle Scholar
  27. 27.
    Roa BB, Garcia CA, Pentao L, et al. Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A. Nat Genet 1993;5:189–194.CrossRefPubMedGoogle Scholar
  28. 28.
    Roa BB, Garcia CA, Suter U, et al. Charcot-Marie-Tooth disease type 1A. Association with a spontaneous point mutation in the PMP22 gene. N Engl J Med 1993;329:96–101.CrossRefPubMedGoogle Scholar
  29. 29.
    Vallat JM, Sindou P, Preux PM, et al. Ultrastructural PMP22 expression in inherited demyelinating neuropathies. Ann Neurol 1996;39:813–817.CrossRefPubMedGoogle Scholar
  30. 30.
    Krajewski KM, Lewis RA, Fuerst DR, et al. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain 2000;123:1516–1527.CrossRefPubMedGoogle Scholar
  31. 31.
    Berciano J, Garcia A, Calleja J, Combarros O. Clinico-electrophysiological correlation of extensor digitorum brevis muscle atrophy in children with charcot-marie-tooth disease 1A duplication. Neuromuscul Disord 2000;10:419–424.CrossRefPubMedGoogle Scholar
  32. 32.
    Suter U, Nave KA. Transgenic mouse models of CMT1A and HNPP. Ann N Y Acad Sci 1999;883:247–253.CrossRefPubMedGoogle Scholar
  33. 33.
    de Waegh S, Brady ST. Altered slow axonal transport and regeneration in a myelin-deficient mutant mouse: the trembler as an in vivo model for Schwann cell-axon interactions. J Neurosci 1990;10:1855–1865.PubMedGoogle Scholar
  34. 34.
    Sahenk Z, Chen L, Mendell JR. Effects of PMP22 duplication and deletions on the axonal cytoskeleton. Ann Neurol 1999;45:16–24.CrossRefPubMedGoogle Scholar
  35. 35.
    Massicotte C, Scherer SS. Neuropathies-translating causes into treatments. In: Neuroscience, Molecular Medicine, and the Therapeutic Transformation of Neurology. In: S.G. Waxman, ed. London: Elsevier Science, 2004: 401-414.Google Scholar
  36. 36.
    Eylar EH, Uyemura K, Brostoff SW, Kitamura K, Ishaque A, Greenfield S. Proposed nomenclature for PNS myelin proteins. Neurochem Res 1979;4:289–293.CrossRefPubMedGoogle Scholar
  37. 37.
    Greenfield S, Brostoff S, Eylar EH, Morell P. Protein composition of myelin of the peripheral nervous system. J Neurochem 1973;20:1207–1216.CrossRefPubMedGoogle Scholar
  38. 38.
    Lemke G, Axel R. Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell 1985;40:501–508.CrossRefPubMedGoogle Scholar
  39. 39.
    Uyemura K, Asou H, Takeda Y. Structure and function of peripheral nerve myelin proteins. Prog Brain Res 1995;105:311–318.CrossRefPubMedGoogle Scholar
  40. 40.
    D’Urso D, Brophy PJ, Staugaitis SM, et al. Protein zero of peripheral nerve myelin: biosynthesis, membrane insertion, and evidence for homotypic interaction. Neuron 1990;4:449–460.CrossRefPubMedGoogle Scholar
  41. 41.
    Eichberg J, Iyer S. Phosphorylation of myelin protein: recent advances. Neurochem Res 1996;21:527–535.CrossRefPubMedGoogle Scholar
  42. 42.
    Filbin MT, Walsh FS, Trapp BD, Pizzey JA, Tennekoon GI. Role of myelin P0 protein as a homophilic adhesion molecule. Nature 1990;344:871–872.CrossRefPubMedGoogle Scholar
  43. 43.
    Xu W, Shy M, Kamholz J, et al. Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination. J Cell Biol 2001;155:439–446.CrossRefPubMedGoogle Scholar
  44. 44.
    Giese KP, Martini R, Lemke G, Soriano P, Schachner M. Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell 1992;71:565–576.CrossRefPubMedGoogle Scholar
  45. 45.
    Wrabetz L, Feltri ML, Quattrini A, et al. P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves. J Cell Biol 2000;148:1021–1034.CrossRefPubMedGoogle Scholar
  46. 46.
    Shy ME, Jani A, Krajewski KM, et al. Phenotypic Clustering in MPZ mutations. Brain 2004;127:371–384.CrossRefPubMedGoogle Scholar
  47. 47.
    Li J, Bai Y, Ianakova E, Grandis M, Uchwat F, Trostinskaia A, Krajewski KM, Garbern J, Kupsky WJ, Shy ME. Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration. J Comp Neurol 2006 Sep 10;498(2):252–265.Google Scholar
  48. 48.
    Bai Y, Ianokova E, Pu Q, Ghandour K, Levinson R, Martin JJ, Ceuterick-de Groote C, Mazanec R, Seeman P, Shy ME, Li J. Effect of an R69C mutation in the myelin protein zero gene on myelination and ion channel subtypes. Arch Neurol 2006 Dec;63(12):1787–1794.Google Scholar
  49. 49.
    Warner LE, Hilz MJ, Appel SH, et al. Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination. Neuron 1996;17:451–460.CrossRefPubMedGoogle Scholar
  50. 50.
    Komiyama A, Ohnishi A, Izawa K, Yamamori S, Ohashi H, Hasegawa O. De novo mutation (Arg98–>Cys) of the myelin P0 gene and uncompaction of the major dense line of the myelin sheath in a severe variant of Charcot-Marie-Tooth disease type 1B. J Neurol Sci 1997;149:103–109.CrossRefPubMedGoogle Scholar
  51. 51.
    Gabreels-Festen AA, Hoogendijk JE, Meijerink PH, et al. Two divergent types of nerve pathology in patients with different P0 mutations in Charcot-Marie-Tooth disease. Neurology 1996;47:761–765.PubMedGoogle Scholar
  52. 52.
    Baxter RV, Ben Othmane K, Rochelle JM, et al. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 2002;30:21–22.CrossRefPubMedGoogle Scholar
  53. 53.
    Cuesta A, Pedrola L, Sevilla T, et al. The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet 2002;30:22–25.CrossRefPubMedGoogle Scholar
  54. 54.
    Pedrola L, Espert A, Valdés-Sánchez T, Sánchez-Piris M, Sirkowski EE, Scherer SS, Fariñas I, Palau F. Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease. J Cell Mol Med. 2008 Apr;12(2):679–689.Google Scholar
  55. 55.
    Niemann A, Ruegg M, La Padula V, Schenone A, Suter U. Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J Cell Biol 2005;170:1067–1078.CrossRefPubMedGoogle Scholar
  56. 56.
    Zhang X, Chow CY, Sahenk Z, Shy ME, Meisler MH, Li J. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain 2008;131:1990–2001.CrossRefPubMedGoogle Scholar
  57. 57.
    Chow CY, Zhang Y, Dowling JJ, et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 2007;448:68–72.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Department of NeurologyWayne State University School of MedicineDetroitUSA

Personalised recommendations