Schwann Cell and Axon: An Interlaced Unit—From Action Potential to Phenotype Expression

  • Felipe A. CourtEmail author
  • Jaime Alvarez
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 949)


Here we propose a model of a peripheral axon with a great deal of autonomy from its cell body—the autonomous axon—but with a substantial dependence on its ensheathing Schwann cell (SC), the axon-SC unit. We review evidence in several fields and show that (i) axons can extend sprouts and grow without the concurrence of the cell body, but regulated by SCs; (ii) axons synthesize their proteins assisted by SCs that supply them with ribosomes and, probably, with mRNAs by way of exosomes; (iii) the molecular organization of the axoplasm, i.e., its phenotype, is regulated by the SC, as illustrated by the axonal microtubular content, which is down-regulated by the SC; and (iv) the axon has a program for self-destruction that is boosted by the SC. The main novelty of this model axon-SC unit is that it breaks with the notion that all proteins of the nerve cell are specified by its own nucleus. The notion of a collaborative specification of the axoplasm by more than one nucleus, which we present here, opens a new dimension in the understanding of the nervous system in health and disease and is also a frame of reference to understand other tissues or cell associations.


Axoplasm Exosomes mRNA Microtubular density Wallerian degeneration 


  1. Aguayo AJ, Bray GM, Rasminsky M, Zwimpfer T, Carter D, Vidal-Sanz M (1990) Synaptic connections made by axons regenerating in the central nervous system of adult mammals. J Exp Biol 153:199–224PubMedGoogle Scholar
  2. Alvarez J (2001) The autonomous axon: a model based on local synthesis of proteins. Biol Res 34(2):103–109PubMedCrossRefGoogle Scholar
  3. Alvarez J, Benech CR (1983) Axoplasmic incorporation of amino acids in a myelinated fiber exceeds that of its soma: a radioautographic study. Exp Neurol 82(1):25–42PubMedCrossRefGoogle Scholar
  4. Alvarez J, Zarour J (1983) Microtubules in short and in long axons of the same caliber: implications for the maintenance of the neuron. Exp Neurol 79(1):283–286PubMedCrossRefGoogle Scholar
  5. Alvarez J, Arredondo F, Espejo F, Williams V (1982) Regulation of axonal microtubules: effect of sympathetic hyperactivity elicited by reserpine. Neuroscience 7(10):2551–2559PubMedCrossRefGoogle Scholar
  6. Alvarez J, Moreno RD, Llanos O, Inestrosa NC, Brandan E, Colby T, Esch FS (1992) Axonal sprouting induced in the sciatic nerve by the amyloid precursor protein (APP) and other antiproteases. Neurosci Lett 144(1–2):130–134PubMedCrossRefGoogle Scholar
  7. Alvarez J, Moreno RD, Inestrosa NC (1995) Mitosis of Schwann cells and demyelination are induced by the amyloid precursor protein and other protease inhibitors in the rat sciatic nerve. Eur J Neurosci 7(1):152–159PubMedCrossRefGoogle Scholar
  8. Alvarez J, Giuditta A, Koenig E (2000) Protein synthesis in axons and terminals: significance for maintenance, plasticity and regulation of phenotype. With a critique of slow transport theory. Prog Neurobiol 62:1–62PubMedCrossRefGoogle Scholar
  9. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29(4):341–345PubMedCrossRefGoogle Scholar
  10. Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, Baran J, Urbanowicz B, Brański P, Ratajczak MZ, Zembala M (2006) Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother 55:808–818PubMedCrossRefGoogle Scholar
  11. Barrientos SA, Martinez NW, Yoo S, Jara JS, Zamorano S, Hetz C, Twiss JL, Alvarez J, Court FA (2011) Axonal degeneration is mediated by the mitochondrial permeability transition pore. J Neurosci 31:359–370CrossRefGoogle Scholar
  12. Benavides E, Alvarez J (1998) Peripheral axons of Wlds mice, which regenerate after a delay of several weeks, do so readily when transcription is inhibited in the distal stump. Neurosci Lett 258(2):77–80PubMedCrossRefGoogle Scholar
  13. Bisby MA, Keen P (1985) The effect of a conditioning lesion on the regeneration rate of peripheral nerve axons containing substance P. Brain Res 336(2):201–206PubMedCrossRefGoogle Scholar
  14. Bittner GD, Mann DW (1976) Differential survival of isolated portions of crayfish axons. Cell Tissue Res 169(3):301–311PubMedCrossRefGoogle Scholar
  15. Blesch A, Tuszynski MH (2009) Spinal cord injury: plasticity, regeneration and the challenge of translational drug development. Trends Neurosci 32(1):41–47PubMedCrossRefGoogle Scholar
  16. Bustos J, Vial JD, Faundez V, Alvarez J (1991) Axons sprout and microtubules increase after local inhibition of RNA synthesis, and microtubules decrease after inhibition of protein synthesis: a morphometric study of rat sural nerves. Eur J Neurosci 3(11):1123–1133PubMedCrossRefGoogle Scholar
  17. Cajal SR (1928) Degeneration and regeneration of the nervous system. Oxford University PressGoogle Scholar
  18. Chattopadhyay S, Shubayev V (2009) MMP-9 controls Schwann cell proliferation and phenotypic remodeling via IGF-1 and ErbB receptor-mediated activation of MEK/ERK pathway. Glia 57(12):1316–1325PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chen Z-L, Yu W-M, Strickland S (2007) Peripheral regeneration. Annu Rev Neurosci 30:209–233PubMedCrossRefGoogle Scholar
  20. Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19(2):43–51PubMedCrossRefGoogle Scholar
  21. Court F, Alvarez J (2000) Nerve regeneration in Wld(s) mice is normalized by actinomycin D. Brain Res 867:1–8PubMedCrossRefGoogle Scholar
  22. Court FA, Alvarez J (2005) Local regulation of the axonal phenotype, a case of merotrophism. Biol Res 38:365–374PubMedCrossRefGoogle Scholar
  23. Court FA, Alvarez J (2011) Slow axoplasmic transport under scrutiny. Biol Res 44:283–293CrossRefGoogle Scholar
  24. Court FA, Coleman MP (2012) Mitochondria as a central sensor for axonal degenerative stimuli. Trends Neurosci 35:364–372PubMedCrossRefGoogle Scholar
  25. Court FA, Hendriks WTJ, Macgillavry HD, Alvarez J, van Minnen J (2008) Schwann cell to axon transfer of ribosomes: toward a novel understanding of the role of glia in the nervous system. J Neurosci 28:11024–11029PubMedCrossRefGoogle Scholar
  26. Court FA, Midha R, Cisterna BA, Grochmal J, Shakhbazau A, Hendriks WT, van Minnen J (2011) Morphological evidence for a transport of ribosomes from Schwann cells to regenerating axons. Glia 59:1529–1539PubMedCrossRefGoogle Scholar
  27. Edström A (1966) Amino acid incorporation in isolated Mauthner nerve fibre of goldfish. J Neurochem 13:315–321CrossRefGoogle Scholar
  28. Ellerton EL, Thompson WJ, Rimer M (2008) Induction of zinc-finger proliferation 1 expression in non-myelinating Schwann cells after denervation. Neuroscience 153(4):975–985. doi: 10.1016/j.neuroscience.2008.02.078 PubMedCrossRefGoogle Scholar
  29. Espejo F, Alvarez J (1986) Microtubules and calibers in normal and regenerating axons of the sural nerve of the rat. J Comp Neurol 250(1):65–72. doi: 10.1002/cne.902500106 PubMedCrossRefGoogle Scholar
  30. Fabrizi C, Kelly BM, Gillespie CS, Schlaepfer WW, Scherer SS, Brophy PJ (1997) Transient expression of the neurofilament proteins NF-L and NF-M by Schwann cells is regulated by axonal contact. J Neurosci Res 50(2):291–299PubMedCrossRefGoogle Scholar
  31. Fadic R, Alvarez J (1986) Calibers and microtubules of sympathetic axons are not subject to trophic control by the preganglionic nerve. Exp Neurol 94(1):237–240PubMedCrossRefGoogle Scholar
  32. Fadic R, Vergara J, Alvarez J (1985) Microtubules and caliber of central and peripheral processes of sensory axons. J Comp Neurol 236(2):258–264. doi: 10.1002/cne.902360209 PubMedCrossRefGoogle Scholar
  33. Faundez V, Cordero ME, Rosso P, Alvarez J (1990) Calibers and microtubules of nerve fibers: differential effect of undernutrition in developing and adult rats. Brain Res 509(2):198–204PubMedCrossRefGoogle Scholar
  34. Filbin MT (2003) Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat Rev Neurosci 4:703–713PubMedCrossRefGoogle Scholar
  35. Friede RL, Samorajski T (1970) Axon caliber related to neurofilaments and microtubules in sciatic nerve fibers of rats and mice. Anat Rec 167(4):379–387. doi: 10.1002/ar.1091670402 PubMedCrossRefGoogle Scholar
  36. Glenn TD, Talbot WS (2013) Signals regulating myelination in peripheral nerves and the Schwann cell response to injury. Curr Opin Neurobiol 23:1041–1048PubMedCrossRefGoogle Scholar
  37. Harding C, Heuser J, Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97(2):329–339PubMedCrossRefGoogle Scholar
  38. Hayworth CR, Moody SE, Chodosh LA, Krieg P, Rimer M, Thompson WJ (2006) Induction of neuregulin signaling in mouse schwann cells in vivo mimics responses to denervation. J Neurosci 26(25):6873–6884. doi: 10.1523/JNEUROSCI.1086-06.2006 PubMedCrossRefGoogle Scholar
  39. Hernandez C, Blackburn E, Alvarez J (1989) Calibre and microtubule content of the non-medullated and myelinated domains of optic nerve axons of rats. Eur J Neurosci 1(6):654–658PubMedCrossRefGoogle Scholar
  40. Hoy RR, Bittner GD, Kennedy D (1967) Regeneration in crustacean motoneurons: evidence for axonal fusion. Science 156(3772):251–252PubMedCrossRefGoogle Scholar
  41. Iñiguez A, Alvarez J (1999) Isolated axons of Wlds mice regrow centralward. Neurosci Lett 268:57–114CrossRefGoogle Scholar
  42. Jessen KR, Mirsky R (2008) Negative regulation of myelination: relevance for development, injury, and demyelinating disease. Glia 56(14):1552–1565PubMedCrossRefGoogle Scholar
  43. Jung H, Yoon BC, Holt CE (2012) Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair. Nat Rev Neurosci 13:308–324PubMedPubMedCentralCrossRefGoogle Scholar
  44. Kang H, Tian L, Mikesh M, Lichtman JW, Thompson WJ (2014) Terminal Schwann cells participate in neuromuscular synapse remodeling during reinnervation following nerve injury. J Neurosci 34(18):6323–6333. doi: 10.1523/JNEUROSCI.4673-13.2014 PubMedPubMedCentralCrossRefGoogle Scholar
  45. Koenig E (1984) Local synthesis of axonal protein. In: Lajtha A (ed) Handbook of neurochemistry, vol 7. Plenum, New York, pp 315–340Google Scholar
  46. Kramer-Albers EM, Bretz N, Tenzer S, Winterstein C, Mobius W, Berger H, Nave KA, Schild H, Trotter J (2007) Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: trophic support for axons? Proteomics Clin Appl 1(11):1446–1461. doi: 10.1002/prca.200700522 PubMedCrossRefGoogle Scholar
  47. Krasne FB, Lee SH (1977) Regenerating afferents establish synapses with a target neuron that lacks its cell body. Science 198(4316):517–519PubMedCrossRefGoogle Scholar
  48. Kun A, Otero L, Sotelo-Silveira JR, Sotelo JR (2007) Ribosomal distributions in axons of mammalian myelinated fibers. J Neurosci Res 85(10):2087–2098. doi: 10.1002/jnr.21340 PubMedCrossRefGoogle Scholar
  49. Li Y, Thompson WJ (2011) Nerve terminal growth remodels neuromuscular synapses in mice following regeneration of the postsynaptic muscle fiber. J Neurosci 31(37):13191–13203. doi: 10.1523/JNEUROSCI.2953-11.2011 PubMedPubMedCentralCrossRefGoogle Scholar
  50. Lin AC, Holt CE (2008) Function and regulation of local axonal translation. Curr Opin Neurobiol 18:60–68PubMedPubMedCentralCrossRefGoogle Scholar
  51. Liu H, Kim Y, Chattopadhyay S, Shubayev I, Dolkas J, Shubayev VI (2010) Matrix metalloproteinase inhibition enhances the rate of nerve regeneration in vivo by promoting dedifferentiation and mitosis of supporting schwann cells. J Neuropathol Exp Neurol 69(4):386–395. doi: 10.1097/NEN.0b013e3181d68d12 PubMedPubMedCentralCrossRefGoogle Scholar
  52. Lopez JM, Alvarez J (1990) The microtubular pattern changes at the spinal cord-root junction and reverts at the root-peripheral nerve junction in sensory and motor fibres of the rat. Eur J Neurosci 2(10):873–878PubMedCrossRefGoogle Scholar
  53. Lopez-Verrilli MA, Court FA (2012) Transfer of vesicles from schwann cells to axons: a novel mechanism of communication in the peripheral nervous system. Front Physiol 3:205PubMedPubMedCentralCrossRefGoogle Scholar
  54. Lopez-Verrilli MA, Court FA (2013) Exosomes: mediators of communication in eukaryotes. Biol Res 46:5–11PubMedCrossRefGoogle Scholar
  55. Lopez-Verrilli MA, Picou F, Court FA (2013) Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system. Glia 61:1795–1806PubMedCrossRefGoogle Scholar
  56. Mason A, Muller KJ (1982) Axon segments sprout at both ends: tracking growth with fluorescent D-peptides. Nature 296(5858):655–657PubMedCrossRefGoogle Scholar
  57. Masuda-Nakagawa LM, Muller KJ, Nicholls JG (1993) Axonal sprouting and laminin appearance after destruction of glial sheaths. Proc Natl Acad Sci USA 90(11):4966–4970PubMedPubMedCentralCrossRefGoogle Scholar
  58. McQuarrie IG, Jacob JM (1991) Conditioning nerve crush accelerates cytoskeletal protein transport in sprouts that form after a subsequent crush. J Comp Neurol 305(1):139–147. doi: 10.1002/cne.903050113 PubMedCrossRefGoogle Scholar
  59. Moreno RD, Inestrosa NC, Culwell AR, Alvarez J (1996) Sprouting and abnormal contacts of nonmedullated axons, and deposition of extracellular material induced by the amyloid precursor protein (APP) and other protease inhibitors. Brain Res 718:13–24PubMedCrossRefGoogle Scholar
  60. Palay SL, Palade GE (1955) The fine structure of neurons. J Biophys Biochem Cytol 1(1):69–88PubMedPubMedCentralCrossRefGoogle Scholar
  61. Pannese E, Ledda M, Arcidiacono G, Rigamonti L, Procacci P (1984a) A comparison of the density of microtubules in the central and peripheral axonal branches of the pseudounipolar neurons of lizard spinal ganglia. Anat Rec 208(4):595–605. doi: 10.1002/ar.1092080415 PubMedCrossRefGoogle Scholar
  62. Pannese E, Procacci P, Ledda M, Arcidiacono G, Rigamonti L (1984b) A quantitative study of microtubules in motor and sensory axons. Acta Anat 118(4):193–200PubMedCrossRefGoogle Scholar
  63. Pannese E, Ledda M, Matsuda S (1988) Nerve fibres with myelinated and unmyelinated portions in dorsal spinal roots. J Neurocytol 17(5):693–700PubMedCrossRefGoogle Scholar
  64. Peters A, Palay S, Webster HdF (1991) Fine structure of the nervous system: neurons and their supporting cells. Oxford Press, New YorkGoogle Scholar
  65. Rigaud M, Gemes G, Barabas M-E, Chernoff DI, Abram SE, Stucky CL, Hogan QH (2008) Species and strain differences in rodent sciatic nerve anatomy: implications for studies of neuropathic pain. Pain 136:188–201PubMedPubMedCentralCrossRefGoogle Scholar
  66. Roberson MD, Toews AD, Goodrum JF, Morell P (1992) Neurofilament and tubulin mRNA expression in Schwann cells. J Neurosci Res 33(1):156–162PubMedCrossRefGoogle Scholar
  67. Russo F, Di Bella S, Nigita G, Macca V, Laganà A, Giugno R, Pulvirenti A, Ferro A (2012) miRandola: extracellular circulating microRNAs database. PLoS ONE 7:e47786. doi: 10.1371/journal.pone.0047786 PubMedPubMedCentralCrossRefGoogle Scholar
  68. Saitua F, Alvarez J (1989) Microtubular packing varies along the course of motor and sensory axons: possible regulation of microtubules by environmental cues. Neurosci Lett 104(3):249–252PubMedCrossRefGoogle Scholar
  69. Schmitte R, Tipold A, Stein VM, Schenk H, Flieshardt C, Grothe C, Haastert K (2010) Genetically modified canine Schwann cells–In vitro and in vivo evaluation of their suitability for peripheral nerve tissue engineering. J Neurosci Methods 186(2):202–208. doi: 10.1016/j.jneumeth.2009.11.023 PubMedCrossRefGoogle Scholar
  70. Serra M, Alvarez J (1989) On the asymmetry of the primary branching of vagal sensory axons: possible role of the supporting tissue. J Comp Neurol 284(1):108–118. doi: 10.1002/cne.902840108 PubMedCrossRefGoogle Scholar
  71. Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476PubMedPubMedCentralCrossRefGoogle Scholar
  72. Smith RS (1973) Microtubule and neurofilament densities in amphibian spinal root nerve fibers: relationship to axoplasmic transport. Can J Physiol Pharmacol 51(11):798–806PubMedCrossRefGoogle Scholar
  73. Tapia M, Inestrosa NC, Alvarez J (1995) Early axonal regeneration: repression by Schwann cells and a protease? Exp Neurol 131(1):124–132PubMedCrossRefGoogle Scholar
  74. Théry C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579PubMedGoogle Scholar
  75. Théry C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593PubMedCrossRefGoogle Scholar
  76. Twiss J, Fainzilber M (2009) Ribosomes in axons - scrounging from the neighbors? Trends Cell Biol 19:236–243PubMedCrossRefGoogle Scholar
  77. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659PubMedCrossRefGoogle Scholar
  78. Valenzuela V, Collyer E, Armentano D, Parsons GB, Court FA, Hetz C (2012) Activation of the unfolded protein response enhances motor recovery after spinal cord injury. Cell Death Dis 3:e272. doi: 10.1038/cddis.2012.8 PubMedCrossRefGoogle Scholar
  79. Vergara J, Serra M, Saitua F, Iturriaga R, Alvarez J (1991) Axonal microtubules: comparative anatomy in vertebrates, including man. J Submicrosc Cytol Pathol 23(3):357–363PubMedGoogle Scholar
  80. Villegas R, Martinez NW, Lillo J, Pihan P, Hernandez D, Twiss JL, Court FA (2014) Calcium release from intra-axonal endoplasmic reticulum leads to axon degeneration through mitochondrial dysfunction. J Neurosci 34(21):7179–7189. doi: 10.1523/JNEUROSCI.4784-13.2014 PubMedPubMedCentralCrossRefGoogle Scholar
  81. Wang D, Sun T (2010) Neural plasticity and functional recovery of human central nervous system with special reference to spinal cord injury. Spinal Cord 49:486–492PubMedCrossRefGoogle Scholar
  82. Windebank AJ, Wood P, Bunge RP, Dyck PJ (1985) Myelination determines the caliber of dorsal root ganglion neurons in culture. J Neurosci 5(6):1563–1569PubMedGoogle Scholar
  83. Yiu G, He Z (2006) Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7:617–627PubMedPubMedCentralCrossRefGoogle Scholar
  84. Yokota R (1984) Occurrence of long non-myelinated axonal segments intercalated in myelinated, presumably sensory axons: electron microscopic observations in the dog atrial endocardium. J Neurocytol 13(1):127–143PubMedCrossRefGoogle Scholar
  85. Yoo S, van Niekerk EA, Merianda TT, Twiss JL (2010) Dynamics of axonal mRNA transport and implications for peripheral nerve regeneration. Exp Neurol 223(1):19–27. doi: 10.1016/j.expneurol.2009.08.011 PubMedCrossRefGoogle Scholar
  86. Zelena J, Lubinska L, Gutmann E (1968) Accumulation of organelles at the ends of interrupted axons. Z Mikrosk Anat Forsch 91(2):200–219CrossRefGoogle Scholar
  87. Zhang J, Zhao F, Wu G, Li Y, Jin X (2010) Functional and histological improvement of the injured spinal cord following transplantation of Schwann cells transfected with NRG1 gene. Anat Rec 293(11):1933–1946. doi: 10.1002/ar.21223 CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Center for Integrative Biology, Universidad MayorSantiagoChile
  2. 2.FONDAP Center for Geroscience, Brain Health and MetabolismSantiagoChile
  3. 3.Millenium Nucleus for Regenerative Biology, Pontificia Universidad Católica de ChileSantiagoChile

Personalised recommendations