Neuroscience Bulletin

, Volume 29, Issue 3, pp 321–332 | Cite as

Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat

Original Article


Wallerian degeneration (WD) remains an important research topic. Many genes are differentially expressed during the process of WD, but the precise mechanisms responsible for these differentiations are not completely understood. In this study, we used microarrays to analyze the expression changes of the distal nerve stump at 0, 1, 4, 7, 14, 21 and 28 days after sciatic nerve injury in rats. The data revealed 6 076 differentially-expressed genes, with 23 types of expression, specifically enriched in genes associated with nerve development and axonogenesis, cytokine biosynthesis, cell differentiation, cytokine/chemokine production, neuron differentiation, cytokinesis, phosphorylation and axon regeneration. Kyoto Encyclopedia of Genes and Genomes pathway analysis gave findings related mainly to the MAPK signaling pathway, the Jak-STAT signaling pathway, the cell cycle, cytokine-cytokine receptor interaction, the p53 signaling pathway and the Wnt signaling pathway. Some key factors were NGF, MAG, CNTF, CTNNA2, p53, JAK2, PLCB1, STAT3, BDNF, PRKC, collagen II, FGF, THBS4, TNC and c-Src, which were further validated by real-time quantitative PCR, Western blot, and immunohistochemistry. Our findings contribute to a better understanding of the functional analysis of differentially-expressed genes in WD and may shed light on the molecular mechanisms of nerve degeneration and regeneration.


Wallerian degeneration rat sciatic nerve expression change microarrays 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    Stoll G, Jander S, Myers RR. Degeneration and regeneration of the peripheral nervous system: from Augustus Waller’s observations to neuroinflammation. J Peripher Nerv Syst 2002, 7: 13–27.PubMedCrossRefGoogle Scholar
  2. [2]
    Waller A. Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibres. Phil Transact Royal Soc London 1850, 140: 423–429.CrossRefGoogle Scholar
  3. [3]
    Ambron RT, Walters ET. Priming events and retrograde injury signals. A new perspective on the cellular and molecular biology of nerve regeneration. Mol Neurobiol 1996, 13: 61–79.PubMedCrossRefGoogle Scholar
  4. [4]
    Boivin A, Pineau I, Barrette B, Filali M, Vallières N, Rivest S, Lacroix S. Toll-like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury. J Neurosci 2007, 27: 12565–12576.PubMedCrossRefGoogle Scholar
  5. [5]
    De S, Trigueros MA, Kalyvas A, David S. Phospholipase A2 plays an important role in myelin breakdown and phagocytosis during Wallerian degeneration. Mol Cell Neurosci 2003, 24: 753–765.PubMedCrossRefGoogle Scholar
  6. [6]
    Girolami EI, Bouhy D, Haber M, Johnson H, David S. Differential expression and potential role of SOCS1 and SOCS3 in Wallerian degeneration in injured peripheral nerve. Exp Neurol 2010, 223: 173–182.PubMedCrossRefGoogle Scholar
  7. [7]
    Guertin AD, Zhang DP, Mak KS, Alberta JA, Kim HA. Microanatomy of axon/glial signaling during Wallerian degeneration. J Neurosci 2005, 25: 3478–3487.PubMedCrossRefGoogle Scholar
  8. [8]
    Martini R, Fischer S, Lopez-Vales R, David S. Interactions between Schwann cells and macrophages in injury and inherited demyelinating disease. Glia 2008, 56: 1566–1577.PubMedCrossRefGoogle Scholar
  9. [9]
    Tofaris GK, Patterson PH, Jessen KR, Mirsky R. Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci 2002, 22: 6696–6703.PubMedGoogle Scholar
  10. [10]
    Navarro X, Vivo M, Valero-Cabre A. Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol 2007, 82: 163–201.PubMedCrossRefGoogle Scholar
  11. [11]
    Parkinson DB, Bhaskaran A, Arthur-Farraj P, Noon LA, Woodhoo A, Lloyd AC, et al. c-Jun is a negative regulator of myelination. J Cell Biol 2008, 181 (4): 625–637.CrossRefGoogle Scholar
  12. [12]
    Kirsch M, Terheggen U, Hofmann HD. Ciliary neurotrophic factor is an early lesion-induced retrograde signal for axotomized facial motoneurons. Mol Cell Neurosci 2003, 24: 130–138.PubMedCrossRefGoogle Scholar
  13. [13]
    Lindholm D, Heumann R, Meyer M, Thoenen H. Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature 1987, 330: 658–659.PubMedCrossRefGoogle Scholar
  14. [14]
    Perrin FE, Lacroix S, Aviles-Trigueros M, David S. Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1a and interleukin-1b in Wallerian degeneration. Brain 2005, 4: 854–866.CrossRefGoogle Scholar
  15. [15]
    Raivich G, Bohatschek M, Da Costa C, Iwata O, Galiano M, Hristova M, et al. The AP-1 transcription factor c-Jun is required for efficient axonal regeneration. Neuron 2004, 43: 57–67.PubMedCrossRefGoogle Scholar
  16. [16]
    Sendtner M, Gotz R, Holtmann B, Thoenen H. Endogenous ciliary neurotrophic factor is a lesion factor for axotomized motoneurons in adult mice. J Neurosci 1997, 17: 6999–7006.PubMedGoogle Scholar
  17. [17]
    Wiklund P, Ekstrom PA, Edstrom A. Mitogen-activated protein kinase inhibition reveals differences in signalling pathways activated by neurotrophin-3 and other growth-stimulating conditions of adult mouse dorsal root ganglia neurons. J Neurosci Res 2002, 67: 62–68.PubMedCrossRefGoogle Scholar
  18. [18]
    Zochodne DW, Levy D, Zwiers H, Sun H, Rubin I, Cheng C, et al. Evidence for nitric oxide and nitric oxide synthase activity in proximal stumps of transected peripheral nerves. Neuroscience 1999, 91: 1515–1527.PubMedCrossRefGoogle Scholar
  19. [19]
    Ramoni MF, Sebastiani P, Kohane IS. Cluster analysis of gene expression dynamics. Proc Natl Acad Sci U S A 2002, 99: 9121–9126.PubMedCrossRefGoogle Scholar
  20. [20]
    Miller LD, Long PM, Wong L, Mukherjee S, McShane LM, Liu ET. Optimal gene expression analysis by microarrays. Cancer Cell 2002, 2: 353–361.PubMedCrossRefGoogle Scholar
  21. [21]
    Kanehisa M, Goto S, Kawashima S, Okuno Y, Hattori M. The KEGG resource for deciphering the genome. Nucleic Acids Res 2004, 32: D277–280.PubMedCrossRefGoogle Scholar
  22. [22]
    Yi M, Horton JD, Cohen JC, Hobbs HH, Stephens RM. WholePathwayScope: a comprehensive pathway-based analysis tool for high-throughput data. BMC Bioinformatics 2006, 7: 30.PubMedCrossRefGoogle Scholar
  23. [23]
    Draghici S, Khatri P, Tarca AL, Amin K, Done A, Voichita C, et al. A systems biology approach for pathway level analysis. Genome Res 2007, 17: 1537–1545.PubMedCrossRefGoogle Scholar
  24. [24]
    Busch H, Camacho-Trullio D, Rogon Z, Breuhahn K, Angel P, Eils R, et al. Gene network dynamics controlling keratinocyte migration. Mol Syst Biol 2008, 4: 199.PubMedCrossRefGoogle Scholar
  25. [25]
    Zhou S, Yu B, Qian T, Yao D, Wang Y, Ding F, et al. Early changes of microRNAs expression in the dorsal root ganglia following rat sciatic nerve transection. Neurosci Lett 2011, 494: 89–93.PubMedCrossRefGoogle Scholar
  26. [26]
    Ghosh A, Greenberg ME. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science 1995, 268: 239–247.PubMedCrossRefGoogle Scholar
  27. [27]
    Hanz S, Perlson E, Willis D, Zheng JQ, Massarwa R, Huerta JJ, et al. Axoplasmic importins enable retrograde injury signaling in lesioned nerve. Neuron 2003, 40: 1095–1104.PubMedCrossRefGoogle Scholar
  28. [28]
    Kim D, Lee S, Lee SJ. Toll-like receptors in peripheral nerve injury and neuropathic pain. Curr Top Microbiol Immunol 2009, 336: 169–186.PubMedCrossRefGoogle Scholar
  29. [29]
    Berti-Mattera LN, Harwalkar S, Hughes B, Wilkins PL, Almhanna K. Proliferative and morphological effects of endothelins in Schwann cells: roles of p38 mitogen-activated protein kinase and Ca(2+)-independent phospholipase A2. J Neurochem 2001, 79: 1136–1148.PubMedCrossRefGoogle Scholar
  30. [30]
    Koehler JA, Moran MF. Regulation of extracellular signalregulated kinase activity by p120 RasGAP does not involve its pleckstrin homology or calcium-dependent lipid binding domains but does require these domains to regulate cell proliferation. Cell Growth Differ 2001, 12: 551–561.PubMedGoogle Scholar
  31. [31]
    Lindwall C, Kanje M. Retrograde axonal transport of JNK signaling molecules influence injury induced nuclear changes in p-c-Jun and ATF3 in adult rat sensory neurons. Mol Cell Neurosci 2005, 29: 269–282.PubMedCrossRefGoogle Scholar
  32. [32]
    Schwaiger FW, Harger G, Schmitt AB, Horvat A, Hager G, Streif R, et al. Peripheral but not central axotomy induces changes in Janus kinases (JAK) and signal transducers and activators of transcription (STAT). Eur J Neurosci 2000, 12: 1165–1176.PubMedCrossRefGoogle Scholar
  33. [33]
    Lee HK, Seo IA, Park HK, Park YM, Ahn KJ, Yoo YH, et al. Nidogen is a prosurvival and promigratory factor for adult Schwann cells. J Neurochem 2007, 102: 686–698.PubMedCrossRefGoogle Scholar
  34. [34]
    Lee N, Neitzel KL, Devlin BK, MacLennan AJ. STAT3 phosphorylation in injured axons before sensory and motor neuron nuclei: potential role for STAT3 as a retrograde signaling transcription factor. J Comp Neurol 2004, 474: 535–545.PubMedCrossRefGoogle Scholar
  35. [35]
    Sheu JY, Kulhanek DJ, Eckenstein FP. Differential patterns of ERK and STAT3 phosphorylation after sciatic nerve transection in the rat. Exp Neurol 2000, 166: 392–402.PubMedCrossRefGoogle Scholar
  36. [36]
    de Bilbao F, Giannakopoulos P, Srinivasan A, Dubois-Dauphin M. In vivo study of motoneuron death induced by nerve injury in mice deficient in the caspase 1/ interleukin-1betaconverting enzyme. Neuroscience 2000, 98 (3): 573–583.CrossRefGoogle Scholar
  37. [37]
    Herdegen T, Waetzig V. The JNK and p38 signal transduction following axotomy. Restor Neurol Neurosci 2001, 19: 29–39.PubMedGoogle Scholar
  38. [38]
    Kuhn G, Lie A, Wilms S, Muller HW. Coexpression of PMP22 gene with MBP and P0 during de novo myelination and nerve repair. Glia 1993, 8: 256–264.PubMedCrossRefGoogle Scholar
  39. [39]
    Shubayev VI, Angert M, Dolkas J, Campana WM, Palenscar K, Myers RR. TNFalpha induced MMP-9 promotes macrophage recruitment into injured peripheral nerve. Mol Cell Neurosci 2006, 31: 407–415.PubMedCrossRefGoogle Scholar
  40. [40]
    Sun W, Oppenheim RW. Response of motoneurons to neonatal sciatic nerve axotomy in Baxknockout mice. Mol Cell Neurosci 2003, 24: 875–886.PubMedCrossRefGoogle Scholar
  41. [41]
    Ugolini G, Raoul C, Ferri A, Haenggeli C, Yamamoto Y, Salaün D, et al. Fas/tumor necrosis factor receptor death signaling is required for axotomy-induced death of motoneurons in vivo. J Neurosci 2003, 23: 8526–8531.PubMedGoogle Scholar
  42. [42]
    Waetzig V, Herdegen T. MEKK1 controls neurite regrowth after experimental injury by balancing ERK1/2 and JNK2 signaling. Mol Cell Neurosci 2005, 30: 67–78.PubMedCrossRefGoogle Scholar
  43. [43]
    Shadiack AM, Sun Y, Zigmond RE. Nerve growth factor antiserum induces axotomy-like changes in neuropeptide expression in intact sympathetic and sensory neurons. J Neurosci 2001, 21: 363–371.PubMedGoogle Scholar
  44. [44]
    Yoo S NM, Fukuda M, Bittner GD, Fishman HM. Plasmalemmal sealing of transected mammalian neurites is a gradual process mediated by Ca(2+)-regulated proteins. J Neurosci Res 2003, 74: 541–551.PubMedCrossRefGoogle Scholar
  45. [45]
    Bosse F, Hasenpusch-Theil K, Küry P, Müller HW. Gene expression profiling reveals that peripheral nerve regeneration is a consequence of both novel injurydependent and reactivated developmental processes. J Neurochem 2006, 96: 1441–1457.PubMedCrossRefGoogle Scholar
  46. [46]
    Makwana M, Raivich G. Molecular mechanisms in successful peripheral regeneration. FEBS J 2005, 272: 2628–2638.PubMedCrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Jiangsu Key Laboratory of NeuroregenerationNantong UniversityNantongChina
  2. 2.School of Life SciencesNantong UniversityNantongChina
  3. 3.Key Laboratory of the People’s Liberation Army, Institute of OrthopaedicsChinese PLA General HospitalBeijingChina

Personalised recommendations