Neuroscience Bulletin

, Volume 29, Issue 4, pp 402–410 | Cite as

Axonal regeneration after spinal cord injury in zebrafish and mammals: differences, similarities, translation



Spinal cord injury (SCI) in mammals results in functional deficits that are mostly permanent due in part to the inability of severed axons to regenerate. Several types of growth-inhibitory molecules expressed at the injury site contribute to this regeneration failure. The responses of axons to these inhibitors vary greatly within and between organisms, reflecting axons’ characteristic intrinsic propensity for regeneration. In the zebrafish (Danio rerio) many but not all axons exhibit successful regeneration after SCI. This review presents and compares the intrinsic and extrinsic determinants of axonal regeneration in the injured spinal cord in mammals and zebrafish. A better understanding of the molecules and molecular pathways underlying the remarkable individualism among neurons in mature zebrafish may support the development of therapies for SCI and their translation to the clinic.


spinal cord injury axonal regeneration growth inhibition functional recovery zebrafish 


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  1. [1]
    Schwab ME, Bartholdi D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 1996, 76: 319–370.PubMedGoogle Scholar
  2. [2]
    Cao HQ, Dong ED. An update on spinal cord injury research. Neurosci Bull 2013, 29: 94–102.PubMedCrossRefGoogle Scholar
  3. [3]
    Becker T, Wullimann MF, Becker CG, Bernhardt RR, Schachner M. Axonal regrowth after spinal cord transection in adult zebrafish. J Comp Neurol 1997, 377: 577–595.PubMedCrossRefGoogle Scholar
  4. [4]
    Hui SP, Dutta A, Ghosh S. Cellular response after crush injury in adult zebrafish spinal cord. Dev Dyn 2010, 239: 2962–2979.PubMedCrossRefGoogle Scholar
  5. [5]
    ten Donkelaar HJ. Development and regenerative capacity of descending supraspinal pathways in tetrapods: a comparative approach. Adv Anat Embryol Cell Biol 2000, 154: iii–ix, 1–145.PubMedGoogle Scholar
  6. [6]
    Becker CG, Becker T (eds). Model organisms in Spinal Cord Regeneration. 1st ed. Weinheim, Germany: Wiley-VCH Verlag GmbH, 2007.Google Scholar
  7. [7]
    Hui SP, Monaghan JR, Voss SR, Ghosh S. Expression pattern of Nogo-A, MAG, and NgR in regenerating urodele spinal cord. Dev Dyn 2013, 242(7): 847–860.PubMedCrossRefGoogle Scholar
  8. [8]
    Becker T, Bernhardt RR, Reinhard E, Wullimann MF, Tongiorgi E, Schachner M. Readiness of zebrafish brain neurons to regenerate a spinal axon correlates with differential expression of specific cell recognition molecules. J Neurosci 1998, 18: 5789–5803.PubMedGoogle Scholar
  9. [9]
    Becker CG, Lieberoth BC, Morellini F, Feldner J, Becker T, Schachner M. L1.1 is involved in spinal cord regeneration in adult zebrafish. J Neurosci 2004, 24: 7837–7842.PubMedCrossRefGoogle Scholar
  10. [10]
    Becker T, Lieberoth BC, Becker CG, Schachner M. Differences in the regenerative response of neuronal cell populations and indications for plasticity in intraspinal neurons after spinal cord transection in adult zebrafish. Mol Cell Neurosci 2005, 30: 265–278.PubMedCrossRefGoogle Scholar
  11. [11]
    Mei F, Christin Chong SY, Chan JR. Myelin-based inhibitors of oligodendrocyte myelination: clues from axonal growth and regeneration. Neurosci Bull 2013, 29: 177–188.PubMedCrossRefGoogle Scholar
  12. [12]
    Shen Y, Tenney AP, Busch SA, Horn KP, Cuascut FX, Liu K, et al. PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 2009, 326: 592–596.PubMedCrossRefGoogle Scholar
  13. [13]
    Fisher D, Xing B, Dill J, Li H, Hoang HH, Zhao Z, et al. Leukocyte common antigen-related phosphatase is a functional receptor for chondroitin sulfate proteoglycan axon growth inhibitors. J Neurosci 2011, 31: 14051–14066.PubMedCrossRefGoogle Scholar
  14. [14]
    Garcia-Alias G, Fawcett JW. Training and anti-CSPG combination therapy for spinal cord injury. Exp Neurol 2012, 235: 26–32.PubMedCrossRefGoogle Scholar
  15. [15]
    Oudega M, Chao OY, Avison DL, Bronson RT, Buchser WJ, Hurtado A, et al. Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury. Exp Neurol 2012, 237: 170–179.PubMedCrossRefGoogle Scholar
  16. [16]
    Galtrey CM, Kwok JC, Carulli D, Rhodes KE, Fawcett JW. Distribution and synthesis of extracellular matrix proteoglycans, hyaluronan, link proteins and tenascin-R in the rat spinal cord. Eur J Neurosci 2008, 27: 1373–1390.PubMedCrossRefGoogle Scholar
  17. [17]
    Snow DM, Letourneau PC. Neurite outgrowth on a step gradient of chondroitin sulfate proteoglycan (CS-PG). J Neurobiol 1992, 23: 322–336.PubMedCrossRefGoogle Scholar
  18. [18]
    Goldshmit Y, Sztal TE, Jusuf PR, Hall TE, Nguyen-Chi M, Currie PD. Fgf-dependent glial cell bridges facilitate spinal cord regeneration in zebrafish. J Neurosci 2012, 32: 7477–7492.PubMedCrossRefGoogle Scholar
  19. [19]
    Becker CG, Becker T. Repellent guidance of regenerating optic axons by chondroitin sulfate glycosaminoglycans in zebrafish. J Neurosci 2002, 22: 842–853.PubMedGoogle Scholar
  20. [20]
    Oertle T, van der Haar ME, Bandtlow CE, Robeva A, Burfeind P, Buss A, et al. Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. J Neurosci 2003, 23: 5393–5406.PubMedGoogle Scholar
  21. [21]
    Huber AB, Weinmann O, Brosamle C, Oertle T, Schwab ME. Patterns of Nogo mRNA and protein expression in the developing and adult rat and after CNS lesions. J Neurosci 2002, 22: 3553–3567.PubMedGoogle Scholar
  22. [22]
    Pernet V, Schwab ME. The role of Nogo-A in axonal plasticity, regrowth and repair. Cell Tissue Res 2012, 349: 97–104.PubMedCrossRefGoogle Scholar
  23. [23]
    Brosamle C, Halpern ME. Nogo-Nogo receptor signalling in PNS axon outgrowth and pathfinding. Mol Cell Neurosci 2009, 40: 401–409.PubMedCrossRefGoogle Scholar
  24. [24]
    Gonzenbach RR, Schwab ME. Disinhibition of neurite growth to repair the injured adult CNS: focusing on Nogo. Cell Mol Life Sci 2008, 65: 161–176.PubMedCrossRefGoogle Scholar
  25. [25]
    Oudega M, Rosano C, Sadi D, Wood PM, Schwab ME, Hagg T. Neutralizing antibodies against neurite growth inhibitor NI-35/250 do not promote regeneration of sensory axons in the adult rat spinal cord. Neuroscience 2000, 100: 873–883.PubMedCrossRefGoogle Scholar
  26. [26]
    Abdesselem H, Shypitsyna A, Solis GP, Bodrikov V, Stuermer CA. No Nogo66- and NgR-mediated inhibition of regenerating axons in the zebrafish optic nerve. J Neurosci 2009, 29: 15489–15498.PubMedCrossRefGoogle Scholar
  27. [27]
    Schnaar RL, Lopez PH. Myelin-associated glycoprotein and its axonal receptors. J Neurosci Res 2009, 87: 3267–3276.PubMedCrossRefGoogle Scholar
  28. [28]
    Mehta NR, Lopez PH, Vyas AA, Schnaar RL. Gangliosides and Nogo receptors independently mediate myelinassociated glycoprotein inhibition of neurite outgrowth in different nerve cells. J Biol Chem 2007, 282: 27875–27886.PubMedCrossRefGoogle Scholar
  29. [29]
    Venkatesh K, Chivatakarn O, Sheu SS, Giger RJ. Molecular dissection of the myelin-associated glycoprotein receptor complex reveals cell type-specific mechanisms for neurite outgrowth inhibition. J Cell Biol 2007, 177: 393–399.PubMedCrossRefGoogle Scholar
  30. [30]
    Lehmann F, Gathje H, Kelm S, Dietz F. Evolution of sialic acid-binding proteins: molecular cloning and expression of fish siglec-4. Glycobiology 2004, 14: 959–968.PubMedCrossRefGoogle Scholar
  31. [31]
    Chen Z, Lee H, Henle SJ, Cheever TR, Ekker SC, Henley JR. Primary neuron culture for nerve growth and axon guidance studies in zebrafish (Danio rerio). PLoS one 2013, 8: e57539.PubMedCrossRefGoogle Scholar
  32. [32]
    Viljetic B, Labak I, Majic S, Stambuk A, Heffer M. Distribution of mono-, di- and trisialo gangliosides in the brain of Actinopterygian fishes. Biochim Biophys Acta 2012, 1820: 1437–1443.PubMedCrossRefGoogle Scholar
  33. [33]
    Lee JK, Geoffroy CG, Chan AF, Tolentino KE, Crawford MJ, Leal MA, et al. Assessing spinal axon regeneration and sprouting in Nogo-, MAG-, and OMgp-deficient mice. Neuron 2010, 66: 663–670.PubMedCrossRefGoogle Scholar
  34. [34]
    Rossi F, Jankovski A, Sotelo C. Differential regenerative response of Purkinje cell and inferior olivary axons confronted with embryonic grafts: environmental cues versus intrinsic neuronal determinants. J Comp Neurol 1995, 359: 663–677.PubMedCrossRefGoogle Scholar
  35. [35]
    Vaudano E, Campbell G, Hunt SP, Lieberman AR. Axonal injury and peripheral nerve grafting in the thalamus and cerebellum of the adult rat: upregulation of c-jun and correlation with regenerative potential. Eur J Neurosci 1998, 10: 2644–2656.PubMedCrossRefGoogle Scholar
  36. [36]
    Benowitz LI, Routtenberg A. GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci 1997, 20: 84–91.PubMedCrossRefGoogle Scholar
  37. [37]
    Zhang Y, Campbell G, Anderson PN, Martini R, Schachner M, Lieberman AR. Molecular basis of interactions between regenerating adult rat thalamic axons and Schwann cells in peripheral nerve grafts i. Neural cell adhesion molecules. J Comp Neurol 1995, 361: 193–209.PubMedCrossRefGoogle Scholar
  38. [38]
    Kamiguchi H, Hlavin ML, Lemmon V. Role of L1 in neural development: what the knockouts tell us. Mol Cell Neurosci 1998, 12: 48–55.PubMedCrossRefGoogle Scholar
  39. [39]
    Ma L, Yu YM, Guo Y, Hart RP, Schachner M. Cysteine- and glycine-rich protein 1a is involved in spinal cord regeneration in adult zebrafish. Eur J Neurosci 2012, 35: 353–365.PubMedCrossRefGoogle Scholar
  40. [40]
    McCurley AT, Callard GV. Time course analysis of gene expression patterns in zebrafish eye during optic nerve regeneration. J Exp Neurosci 2010, 2010: 17–33.PubMedGoogle Scholar
  41. [41]
    Tran TC, Singleton C, Fraley TS, Greenwood JA. Cysteinerich protein 1 (CRP1) regulates actin filament bundling. BMC Cell Biol 2005, 6: 45.PubMedCrossRefGoogle Scholar
  42. [42]
    Ma L, Greenwood JA, Schachner M. CRP1, a protein localized in filopodia of growth cones, is involved in dendritic growth. J Neurosci 2011, 31: 16781–16791.PubMedCrossRefGoogle Scholar
  43. [43]
    Stoeckli ET, Kuhn TB, Duc Co, Ruegg MA, Sonderegger P. The axonally secreted protein axonin-1 is a potent substratum for neurite growth. J Cell Biol 1991, 112: 449–455.PubMedCrossRefGoogle Scholar
  44. [44]
    Wolfer DP, Giger RJ, Stagliar M, Sonderegger P, Lipp HP. Expression of the axon growth-related neural adhesion molecule TAG-1/axonin-1 in the adult mouse brain. Anat Embryol (Berl) 1998, 197: 177–185.CrossRefGoogle Scholar
  45. [45]
    Lin JF, Pan HC, Ma LP, Shen YQ, Schachner M. The cell neural adhesion molecule contactin-2 (TAG-1) is beneficial for functional recovery after spinal cord injury in adult zebrafish. PLoS One 2012, 7 (12): e52376.CrossRefGoogle Scholar
  46. [46]
    Smith PD, Sun F, Park KK, Cai B, Wang C, Kuwako K, et al. SoCS3 deletion promotes optic nerve regeneration in vivo. Neuron 2009, 64: 617–623.PubMedCrossRefGoogle Scholar
  47. [47]
    Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mToR pathway. Science 2008, 322: 963–966.PubMedCrossRefGoogle Scholar
  48. [48]
    Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci 2010, 13: 1075–1081.PubMedCrossRefGoogle Scholar
  49. [49]
    Abe N, Borson SH, Gambello MJ, Wang F, Cavalli V. Mammalian target of rapamycin (mToR) activation increases axonal growth capacity of injured peripheral nerves. J Biol Chem 2010, 285: 28034–28043.PubMedCrossRefGoogle Scholar
  50. [50]
    Chugani DC, Rome LH, Kedersha NL. Evidence that vault ribonucleoprotein particles localize to the nuclear pore complex. J Cell Sci 1993, 106(Pt 1): 23–29.PubMedGoogle Scholar
  51. [51]
    Pan HC, Lin JF, Ma LP, Shen YQ, Schachner M. Major vault protein promotes locomotor recovery and regeneration after spinal cord injury in adult zebrafish. Eur J Neurosci 2013, 37: 203–211.PubMedCrossRefGoogle Scholar
  52. [52]
    Komori N, Takemori N, Kim HK, Singh A, Hwang SH, Foreman RD, et al. Proteomics study of neuropathic and nonneuropathic dorsal root ganglia: altered protein regulation following segmental spinal nerve ligation injury. Physiol Genomics 2007, 29: 215–230.PubMedGoogle Scholar
  53. [53]
    Li JY, Volknandt W, Dahlstrom A, Herrmann C, Blasi J, Das B, et al. Axonal transport of ribonucleoprotein particles (vaults). Neuroscience 1999, 91: 1055–1065.PubMedCrossRefGoogle Scholar
  54. [54]
    Steiner E, Holzmann K, Pirker C, Elbling L, Micksche M, Sutterluty H, et al. The major vault protein is responsive to and interferes with interferon-gamma-mediated STAT1 signals. J Cell Sci 2006, 119: 459–469.PubMedCrossRefGoogle Scholar
  55. [55]
    Minaguchi T, Waite KA, Eng C. Nuclear localization of PTEN is regulated by Ca(2+) through a tyrosil phosphorylation-independent conformational modification in major vault protein. Cancer Res 2006, 66: 11677–11682.PubMedCrossRefGoogle Scholar
  56. [56]
    Yu YM, Gibbs KM, Davila J, Campbell N, Sung S, Todorova TI, et al. MicroRNA miR-133b is essential for functional recovery after spinal cord injury in adult zebrafish. Eur J Neurosci 2011, 33: 1587–1597.PubMedCrossRefGoogle Scholar
  57. [57]
    Liu NK, Wang XF, Lu QB, Xu XM. Altered microRNA expression following traumatic spinal cord injury. Exp Neurol 2009, 219: 424–429.PubMedCrossRefGoogle Scholar
  58. [58]
    Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med 2007, 13: 613–618.PubMedCrossRefGoogle Scholar
  59. [59]
    Dong DL, Chen C, Huo R, Wang N, Li Z, Tu YJ, et al. Reciprocal repression between microRNA-133 and calcineurin regulates cardiac hypertrophy: a novel mechanism for progressive cardiac hypertrophy. Hypertension 2010, 55: 946–952.PubMedCrossRefGoogle Scholar
  60. [60]
    Xu C, Lu Y, Pan Z, Chu W, Luo X, Lin H, et al. The musclespecific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes. J Cell Sci 2007, 120: 3045–3052.PubMedCrossRefGoogle Scholar
  61. [61]
    McKerracher L, Ferraro GB, Fournier AE. Rho signaling and axon regeneration. int Rev Neurobiol 2012, 105: 117–140.PubMedCrossRefGoogle Scholar
  62. [62]
    Diaz-Ruiz A, Vergara P, Perez-Severiano F, Segovia J, Guizar-Sahagún G, Ibarra A, et al. Cyclosporin-A inhibits constitutive nitric oxide synthase activity and neuronal and endothelial nitric oxide synthase expressions after spinal cord injury in rats. Neurochem Res 2005, 30: 245–251.PubMedCrossRefGoogle Scholar
  63. [63]
    Colak A, Karaoğlan A, Barut S, Köktürk S, Akyildiz AI, Taşyürekli M. Neuroprotection and functional recovery after application of the caspase-9 inhibitor z-LEHD-fmk in a rat model of traumatic spinal cord injury. J Neurosurg Spine 2005, 2: 327–334.PubMedCrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Physical Medicine & RehabilitationUniversity of PittsburghPittsburghUSA
  2. 2.Department of NeurobiologyUniversity of PittsburghPittsburghUSA
  3. 3.Department of BioengineeringUniversity of PittsburghPittsburghUSA
  4. 4.Department of School of Science, Technology and Engineering ManagementSt. Thomas UniversityMiami GardensUSA

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