Advertisement

Cellular and Molecular Life Sciences

, Volume 76, Issue 21, pp 4355–4368 | Cite as

KIF2A characterization after spinal cord injury

  • Oscar SeiraEmail author
  • Jie Liu
  • Peggy Assinck
  • Matt Ramer
  • Wolfram Tetzlaff
Original Article

Abstract

Axons in the central nervous system (CNS) typically fail to regenerate after injury. This failure is multi-factorial and caused in part by disruption of the axonal cytoskeleton. The cytoskeleton, in particular microtubules (MT), plays a critical role in axonal transport and axon growth during development. In this regard, members of the kinesin superfamily of proteins (KIFs) regulate the extension of primary axons toward their targets and control the growth of collateral branches. KIF2A negatively regulates axon growth through MT depolymerization. Using three different injury models to induce SCI in adult rats, we examined the temporal and cellular expression of KIF2A in the injured spinal cord. We observed a progressive increase of KIF2A expression with maximal levels at 10 days to 8 weeks post-injury as determined by Western blot analysis. KIF2A immunoreactivity was present in axons, spinal neurons and mature oligodendrocytes adjacent to the injury site. Results from the present study suggest that KIF2A at the injured axonal tips may contribute to neurite outgrowth inhibition after injury, and that its increased expression in inhibitory spinal neurons adjacent to the injury site might contribute to an intrinsic wiring-control mechanism associated with neuropathic pain. Further studies will determine whether KIF2A may be a potential target for the development of regeneration-promoting or pain-preventing therapies.

Keywords

Kinesin Cytoskeleton Spinal cord injury Regeneration Neuropathic pain 

Notes

Acknowledgements

We thank all laboratory members for their help and suggestions, and especially we thank Dr. W. Plunet and Dr. B. Hilton for their valuable feedback on and input into the manuscript and review. Funding was provided by a Seed Grant from the Rick Hansen Foundation to the Blusson Integrated Cure Partnership. W. T. holds the John and Penny Ryan British Columbia leadership chair in spinal cord research.

Supplementary material

18_2019_3116_MOESM1_ESM.docx (5.6 mb)
Supplementary material 1 (DOCX 5752 kb)

References

  1. 1.
    Anderson TE, Stokes BT (1992) Experimental models for spinal cord injury research: physical and physiological considerations. J Neurotrauma 9(Suppl 1):S135–S142PubMedGoogle Scholar
  2. 2.
    Attal N, Bouhassira D (2004) Can pain be more or less neuropathic? Pain 110(3):510–511PubMedGoogle Scholar
  3. 3.
    Baas PW, Matamoros AJ (2015) Inhibition of kinesin-5 improves regeneration of injured axons by a novel microtubule-based mechanism. Neural Regen Res 10(6):845–849PubMedPubMedCentralGoogle Scholar
  4. 4.
    Barbeau H, Fung J et al (2002) A review of the adaptability and recovery of locomotion after spinal cord injury. Prog Brain Res 137:9–25PubMedGoogle Scholar
  5. 5.
    Borisoff JF, Chan CC et al (2003) Suppression of Rho-kinase activity promotes axonal growth on inhibitory CNS substrates. Mol Cell Neurosci 22(3):405–416PubMedGoogle Scholar
  6. 6.
    Bradke F, Fawcett JW et al (2012) Assembly of a new growth cone after axotomy: the precursor to axon regeneration. Nat Rev Neurosci 13(3):183–193PubMedGoogle Scholar
  7. 7.
    Broggini T, Schnell L et al (2016) Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury. Aging (Albany NY) 8(10):2463–2487Google Scholar
  8. 8.
    Casey KL (1992) 1991 Bonica Lecture. Central pain syndromes: current views on pathophysiology, diagnosis, and treatment. Reg Anesth 17(2):59–68PubMedGoogle Scholar
  9. 9.
    Chen K, Liu J et al (2016) Differential histopathological and behavioral outcomes eight weeks after rat spinal cord injury by contusion, dislocation, and distraction mechanisms. J Neurotrauma 33(18):1667–1684PubMedPubMedCentralGoogle Scholar
  10. 10.
    Chen S, Yang G et al (2016) A comparative study of three interneuron types in the rat spinal cord. PLoS One 11(9):e0162969PubMedPubMedCentralGoogle Scholar
  11. 11.
    Correas I, Diaz-Nido J et al (1992) Microtubule-associated protein tau is phosphorylated by protein kinase C on its tubulin binding domain. J Biol Chem 267(22):15721–15728PubMedGoogle Scholar
  12. 12.
    Costigan M, Scholz J et al (2009) Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 32:1–32PubMedPubMedCentralGoogle Scholar
  13. 13.
    Dent EW, Gertler FB (2003) Cytoskeletal dynamics and transport in growth cone motility and axon guidance. Neuron 40(2):209–227PubMedGoogle Scholar
  14. 14.
    Drewes G, Trinczek B et al (1995) Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. J Biol Chem 270(13):7679–7688PubMedGoogle Scholar
  15. 15.
    Dubner R (1991) Pain and hyperalgesia following tissue injury: new mechanisms and new treatments. Pain 44(3):213–214PubMedGoogle Scholar
  16. 16.
    Fallah Z, Clowry GJ (1999) The effect of a peripheral nerve lesion on calbindin D28k immunoreactivity in the cervical ventral horn of developing and adult rats. Exp Neurol 156(1):111–120PubMedGoogle Scholar
  17. 17.
    Finnerup NB, Jensen TS (2004) Spinal cord injury pain—mechanisms and treatment. Eur J Neurol 11(2):73–82PubMedGoogle Scholar
  18. 18.
    Forgione N, Chamankhah M et al (2017) A mouse model of bilateral cervical contusion-compression spinal cord injury. J Neurotrauma 34(6):1227–1239PubMedGoogle Scholar
  19. 19.
    Fouad K, Torres-Espín A, Fenrich KK (2019) Mechanisms of behavioral changes after spinal cord injury. Disord Nerv Syst Mot Syst  https://doi.org/10.1093/acrefore/9780190264086.013.245 CrossRefGoogle Scholar
  20. 20.
    Fournier AE, Takizawa BT et al (2003) Rho kinase inhibition enhances axonal regeneration in the injured CNS. J Neurosci 23(4):1416–1423PubMedPubMedCentralGoogle Scholar
  21. 21.
    Franker MA, Hoogenraad CC (2013) Microtubule-based transport—basic mechanisms, traffic rules and role in neurological pathogenesis. J Cell Sci 126(Pt 11):2319–2329PubMedGoogle Scholar
  22. 22.
    Fujikura K, Setsu T et al (2013) Kif14 mutation causes severe brain malformation and hypomyelination. PLoS One 8(1):e53490PubMedPubMedCentralGoogle Scholar
  23. 23.
    Ghosh-Roy A, Goncharov A et al (2012) Kinesin-13 and tubulin posttranslational modifications regulate microtubule growth in axon regeneration. Dev Cell 23(4):716–728PubMedPubMedCentralGoogle Scholar
  24. 24.
    Goold RG, Gordon-Weeks PR (2004) Glycogen synthase kinase 3beta and the regulation of axon growth. Biochem Soc Trans 32(Pt 5):809–811PubMedGoogle Scholar
  25. 25.
    Gordon-Weeks PR, Fournier AE (2014) Neuronal cytoskeleton in synaptic plasticity and regeneration. J Neurochem 129(2):206–212PubMedGoogle Scholar
  26. 26.
    Gumy LF, Chew DJ et al (2013) The kinesin-2 family member KIF3C regulates microtubule dynamics and is required for axon growth and regeneration. J Neurosci 33(28):11329–11345PubMedPubMedCentralGoogle Scholar
  27. 27.
    Hirokawa N, Noda Y et al (2009) Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol 10(10):682–696PubMedGoogle Scholar
  28. 28.
    Hirokawa N, Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6(3):201–214PubMedGoogle Scholar
  29. 29.
    Hirokawa N, Tanaka Y (2015) Kinesin superfamily proteins (KIFs): various functions and their relevance for important phenomena in life and diseases. Exp Cell Res 334(1):16–25PubMedGoogle Scholar
  30. 30.
    Homma N, Takei Y et al (2003) Kinesin superfamily protein 2A (KIF2A) functions in suppression of collateral branch extension. Cell 114(2):229–239PubMedGoogle Scholar
  31. 31.
    Homma N, Zhou R et al (2018) KIF2A regulates the development of dentate granule cells and postnatal hippocampal wiring. Elife.  https://doi.org/10.7554/eLife.30935 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hur EM, Saijilafu et al (2012) Growing the growth cone: remodeling the cytoskeleton to promote axon regeneration. Trends Neurosci 35(3):164–174PubMedGoogle Scholar
  33. 33.
    Kapitein LC, Hoogenraad CC (2015) Building the neuronal microtubule cytoskeleton. Neuron 87(3):492–506PubMedGoogle Scholar
  34. 34.
    Kevenaar JT, Hoogenraad CC (2015) The axonal cytoskeleton: from organization to function. Front Mol Neurosci 8:44PubMedPubMedCentralGoogle Scholar
  35. 35.
    Kim YT, Hur EM et al (2011) Role of GSK3 signaling in neuronal morphogenesis. Front Mol Neurosci 4:48PubMedPubMedCentralGoogle Scholar
  36. 36.
    Kitada M, Rowitch DH (2006) Transcription factor co-expression patterns indicate heterogeneity of oligodendroglial subpopulations in adult spinal cord. Glia 54(1):35–46PubMedGoogle Scholar
  37. 37.
    Labrakakis C, Lorenzo LE et al (2009) Inhibitory coupling between inhibitory interneurons in the spinal cord dorsal horn. Mol Pain 5:24PubMedPubMedCentralGoogle Scholar
  38. 38.
    Lieu A, Tenorio G et al (2013) Protein kinase C gamma (PKCgamma) as a novel marker to assess the functional status of the corticospinal tract in experimental autoimmune encephalomyelitis (EAE). J Neuroimmunol 256(1–2):43–48PubMedGoogle Scholar
  39. 39.
    Lin S, Liu M et al (2011) Inhibition of kinesin-5, a microtubule-based motor protein, as a strategy for enhancing regeneration of adult axons. Traffic 12(3):269–286PubMedPubMedCentralGoogle Scholar
  40. 40.
    Liu G, Dwyer T (2014) Microtubule dynamics in axon guidance. Neurosci Bull 30(4):569–583PubMedPubMedCentralGoogle Scholar
  41. 41.
    Liu T, Lee SY (2013) Phosphatidylinositol 4-phosphate 5-kinase alpha negatively regulates nerve growth factor-induced neurite outgrowth in PC12 cells. Exp Mol Med 45:e16PubMedPubMedCentralGoogle Scholar
  42. 42.
    Lyons DA, Naylor SG et al (2009) Kif1b is essential for mRNA localization in oligodendrocytes and development of myelinated axons. Nat Genet 41(7):854–858PubMedPubMedCentralGoogle Scholar
  43. 43.
    Maor-Nof M, Homma N et al (2013) Axonal pruning is actively regulated by the microtubule-destabilizing protein kinesin superfamily protein 2A. Cell Rep 3(4):971–977PubMedGoogle Scholar
  44. 44.
    Marques S, Zeisel A et al (2016) Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science 352(6291):1326–1329PubMedPubMedCentralGoogle Scholar
  45. 45.
    Meijering E, Jacob M et al (2004) Design and validation of a tool for neurite tracing and analysis in fluorescence microscopy images. Cytom A 58(2):167–176Google Scholar
  46. 46.
    Metz GA, Curt A et al (2000) Validation of the weight-drop contusion model in rats: a comparative study of human spinal cord injury. J Neurotrauma 17(1):1–17PubMedGoogle Scholar
  47. 47.
    Monteiro MI, Ahlawat S et al (2012) The kinesin-3 family motor KLP-4 regulates anterograde trafficking of GLR-1 glutamate receptors in the ventral nerve cord of Caenorhabditis elegans. Mol Biol Cell 23(18):3647–3662PubMedPubMedCentralGoogle Scholar
  48. 48.
    Morfini G, Quiroga S et al (1997) Suppression of KIF2 in PC12 cells alters the distribution of a growth cone nonsynaptic membrane receptor and inhibits neurite extension. J Cell Biol 138(3):657–669PubMedPubMedCentralGoogle Scholar
  49. 49.
    Mori M, Kose A et al (1990) Immunocytochemical localization of protein kinase C subspecies in the rat spinal cord: light and electron microscopic study. J Comp Neurol 299(2):167–177PubMedGoogle Scholar
  50. 50.
    Nardone R, Holler Y et al (2015) Serotonergic transmission after spinal cord injury. J Neural Transm (Vienna) 122(2):279–295Google Scholar
  51. 51.
    Neumann S, Braz JM et al (2008) Innocuous, not noxious, input activates PKCgamma interneurons of the spinal dorsal horn via myelinated afferent fibers. J Neurosci 28(32):7936–7944PubMedPubMedCentralGoogle Scholar
  52. 52.
    Ni Y, Nawabi H et al (2014) Characterization of long descending premotor propriospinal neurons in the spinal cord. J Neurosci 34(28):9404–9417PubMedPubMedCentralGoogle Scholar
  53. 53.
    Noda Y, Niwa S et al (2012) Phosphatidylinositol 4-phosphate 5-kinase alpha (PIPKalpha) regulates neuronal microtubule depolymerase kinesin, KIF2A and suppresses elongation of axon branches. Proc Natl Acad Sci USA 109(5):1725–1730PubMedGoogle Scholar
  54. 54.
    Noda Y, Sato-Yoshitake R et al (1995) KIF2 is a new microtubule-based anterograde motor that transports membranous organelles distinct from those carried by kinesin heavy chain or KIF3A/B. J Cell Biol 129(1):157–167PubMedGoogle Scholar
  55. 55.
    Ogawa T, Hirokawa N (2015) Microtubule destabilizer KIF2A undergoes distinct site-specific phosphorylation cascades that differentially affect neuronal morphogenesis. Cell Rep 12(11):1774–1788PubMedGoogle Scholar
  56. 56.
    Petitjean H, Pawlowski SA et al (2015) Dorsal horn parvalbumin neurons are gate-keepers of touch-evoked pain after nerve injury. Cell Rep 13(6):1246–1257PubMedPubMedCentralGoogle Scholar
  57. 57.
    Pierrot-Deseilligny E, Bussel B (1975) Evidence for recurrent inhibition by motoneurons in human subjects. Brain Res 88(1):105–108PubMedGoogle Scholar
  58. 58.
    Polgar E, Fowler JH et al (1999) The types of neuron which contain protein kinase C gamma in rat spinal cord. Brain Res 833(1):71–80PubMedGoogle Scholar
  59. 59.
    Porseva VV, Shilkin VV et al (2014) Calbindin-containing neurons of the ventral horn of murine spinal cord gray matter. Morfologiia 146(4):21–25PubMedGoogle Scholar
  60. 60.
    Porseva VV, Shilkin VV et al (2014) Subpopulation of calbindin-immunoreactive interneurons in the dorsal horn of the mice spinal cord. Tsitologiia 56(8):612–618PubMedGoogle Scholar
  61. 61.
    Ren K, Ruda MA (1994) A comparative study of the calcium-binding proteins calbindin-D28K, calretinin, calmodulin and parvalbumin in the rat spinal cord. Brain Res Brain Res Rev 19(2):163–179PubMedGoogle Scholar
  62. 62.
    Rishal I, Fainzilber M (2014) Axon-soma communication in neuronal injury. Nat Rev Neurosci 15(1):32–42PubMedGoogle Scholar
  63. 63.
    Rosenberg LJ, Zai LJ et al (2005) Chronic alterations in the cellular composition of spinal cord white matter following contusion injury. Glia 49(1):107–120PubMedGoogle Scholar
  64. 64.
    Sakakibara A, Ando R et al (2013) Microtubule dynamics in neuronal morphogenesis. Open Biol 3(7):130061PubMedPubMedCentralGoogle Scholar
  65. 65.
    Scacheri PC, Rozenblatt-Rosen O et al (2004) Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells. Proc Natl Acad Sci USA 101(7):1892–1897PubMedGoogle Scholar
  66. 66.
    Seira O, del Rio JA (2014) Glycogen synthase kinase 3 beta (GSK3 beta) at the tip of neuronal development and regeneration. Mol Neurobiol 49(2):931–944PubMedGoogle Scholar
  67. 67.
    Sparling JS, Bretzner F et al (2015) Schwann cells generated from neonatal skin-derived precursors or neonatal peripheral nerve improve functional recovery after acute transplantation into the partially injured cervical spinal cord of the rat. J Neurosci 35(17):6714–6730PubMedPubMedCentralGoogle Scholar
  68. 68.
    Vale RD (2003) The molecular motor toolbox for intracellular transport. Cell 112(4):467–480PubMedPubMedCentralGoogle Scholar
  69. 69.
    van Bruggen D, Agirre E et al (2017) Single-cell transcriptomic analysis of oligodendrocyte lineage cells. Curr Opin Neurobiol 47:168–175PubMedGoogle Scholar
  70. 70.
    van den Berg R, Hoogenraad CC (2012) Molecular motors in cargo trafficking and synapse assembly. Adv Exp Med Biol 970:173–196PubMedGoogle Scholar
  71. 71.
    Xu C, Klaw MC et al (2015) Pharmacologically inhibiting kinesin-5 activity with monastrol promotes axonal regeneration following spinal cord injury. Exp Neurol 263:172–176PubMedGoogle Scholar
  72. 72.
    Yamazaki M, Miyazaki H et al (2002) Phosphatidylinositol 4-phosphate 5-kinase is essential for ROCK-mediated neurite remodeling. J Biol Chem 277(19):17226–17230PubMedGoogle Scholar
  73. 73.
    Yu X, Wen H et al (2013) Temporal and spatial expression of KIF3B after acute spinal cord injury in adult rats. J Mol Neurosci 49(2):387–394PubMedGoogle Scholar
  74. 74.
    Zacharova G, Sojka D et al (2009) Changes of parvalbumin expression in the spinal cord after peripheral inflammation. Physiol Res 58(3):435–442PubMedGoogle Scholar
  75. 75.
    Zai LJ, Wrathall JR (2005) Cell proliferation and replacement following contusive spinal cord injury. Glia 50(3):247–257PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Oscar Seira
    • 1
    • 2
    Email author
  • Jie Liu
    • 1
  • Peggy Assinck
    • 1
    • 3
    • 5
  • Matt Ramer
    • 1
    • 2
  • Wolfram Tetzlaff
    • 1
    • 2
    • 4
  1. 1.International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord CentreUniversity of British Columbia (UBC)VancouverCanada
  2. 2.Department of ZoologyUniversity of British Columbia (UBC)VancouverCanada
  3. 3.Graduate Program in NeuroscienceUniversity of British Columbia (UBC)VancouverCanada
  4. 4.Department of SurgeryUniversity of British Columbia (UBC)VancouverCanada
  5. 5.MRC Centre for Regenerative MedicineThe University of EdinburghEdinburghUK

Personalised recommendations