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Intrinsic Neuronal Mechanisms in Axon Regeneration After Spinal Cord Injury

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Abstract

Axon transection and failure of axon regeneration after spinal cord injury result in permanent functional deficits. Previous focus on blocking the inhibitory environment turns out to be insufficient to achieve robust axon regeneration in the central nervous system (CNS). Loss of intrinsic axon growth ability in adult CNS neurons might also play a critical role in underlying such regeneration failure. Based on recently revealed mechanistic insights about intrinsic ability controls, several experimental strategies have been devised to promote injured axons to regenerate with large quantities and long distance, and may provide important therapeutic approaches to recovering function after spinal cord injury.

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References

  1. Nielson JL, Sears-Kraxberger I, Strong MK, Wong JK, Willenberg R, Steward O. Unexpected survival of neurons of origin of the pyramidal tract after spinal cord injury. J Neurosci. 2010;30:11516–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kwon BK, Liu J, Messerer C, Kobayashi NR, McGraw J, Oschipok L, et al. Survival and regeneration of rubrospinal neurons 1 year after spinal cord injury. Proc Natl Acad Sci U S A. 2002;99:3246–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Houle JD, Ye JH. Survival of chronically-injured neurons can be prolonged by treatment with neurotrophic factors. Neuroscience. 1999;94(3):929–36.

    Article  CAS  PubMed  Google Scholar 

  4. Ramon y Cajal S. Degeneration and regeneration of the nervous system. London: Oxford University Press; 1928.

    Google Scholar 

  5. Aguayo AJ, David S, Bray GM. Influences of the glial environment on the elongation of axons after injury: transplantation studies in adult rodents. J Exp Biol. 1981;95:231–40.

    CAS  PubMed  Google Scholar 

  6. David S, Aguayo AJ. Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science. 1981;214(4523):931–3.

    Article  CAS  PubMed  Google Scholar 

  7. Richardson PM, Issa VM, Aguayo AJ. Regeneration of long spinal axons in the rat. J Neurocytol. 1984;13(1):165–82.

    Article  CAS  PubMed  Google Scholar 

  8. Case LC, Tessier-Lavigne M. Regeneration of the adult central nervous system. Curr Biol. 2005;15(18):R749–53.

    Article  CAS  PubMed  Google Scholar 

  9. Filbin MT. Recapitulate development to promote axonal regeneration: good or bad approach? Philos Trans R Soc Lond Ser B Biol Sci. 2006;361(1473):1565–74.

    Article  CAS  Google Scholar 

  10. Fitch MT, Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Exp Neurol. 2008;209(2):294–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Garcia-Alias G, Fawcett JW. Training and anti-CSPG combination therapy for spinal cord injury. Exp Neurol. 2012;235(1):26–32.

    Article  CAS  PubMed  Google Scholar 

  12. Harel NY, Strittmatter SM. Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nat Rev Neurosci. 2006;7(8):603–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schwab ME. Nogo and axon regeneration. Curr Opin Neurobiol. 2004;14(1):118–24.

    Article  CAS  PubMed  Google Scholar 

  14. Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci. 2006;7(8):617–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Silver J, Schwab ME, Popovich PG. Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb Perspect Biol. 2014 Dec 4.

    Google Scholar 

  16. 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(5):663–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lee JK, Chan AF, Luu SM, Zhu Y, Ho C, Tessier-Lavigne M, et al. Reassessment of corticospinal tract regeneration in Nogo-deficient mice. J Neurosci. 2009;29(27):8649–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lang BT, Cregg JM, DePaul MA, Tran AP, Xu K, Dyck SM, et al. Modulation of the proteoglycan receptor PTPsigma promotes recovery after spinal cord injury. Nature. 2014.

    Google Scholar 

  19. Aguayo AJ, Rasminsky M, Bray GM, Carbonetto S, McKerracher L, Villegas-Perez MP, et al. Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond Ser B Biol Sci. 1991;331(1261):337–43.

    Article  CAS  Google Scholar 

  20. Liu K, Tedeschi A, Park KK, He Z. Neuronal intrinsic mechanisms of axon regeneration. Annu Rev Neurosci. 2011;34:131–52.

    Article  PubMed  Google Scholar 

  21. Chen DF, Jhaveri S, Schneider GE. Intrinsic changes in developing retinal neurons result in regenerative failure of their axons. Proc Natl Acad Sci U S A. 1995;92(16):7287–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Goldberg JL, Espinosa JS, Xu Y, Davidson N, Kovacs GT, Barres BA. Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity. Neuron. 2002;33(5):689–702.

    Article  CAS  PubMed  Google Scholar 

  23. Bjorklund A, Stenevi U. Intracerebral neural implants: neuronal replacement and reconstruction of damaged circuitries. Annu Rev Neurosci. 1984;7:279–308.

    Article  CAS  PubMed  Google Scholar 

  24. Blackmore M, Letourneau PC. Changes within maturing neurons limit axonal regeneration in the developing spinal cord. J Neurobiol. 2006;66(4):348–60.

    Article  CAS  PubMed  Google Scholar 

  25. Dusart I, Airaksinen MS, Sotelo C. Purkinje cell survival and axonal regeneration are age dependent: an in vitro study. J Neurosci. 1997;17(10):3710–26.

    CAS  PubMed  Google Scholar 

  26. Li D, Field PM, Raisman G. Failure of axon regeneration in postnatal rat entorhinohippocampal slice coculture is due to maturation of the axon, not that of the pathway or target. Eur J Neurosci. 1995;7(6):1164–71.

    Article  CAS  PubMed  Google Scholar 

  27. Goldberg JL, Klassen MP, Hua Y, Barres BA. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science. 2002;296(5574):1860–4.

    Article  CAS  PubMed  Google Scholar 

  28. Chen DF, Schneider GE, Martinou JC, Tonegawa S. Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature. 1997;385(6615):434–9.

    Article  CAS  PubMed  Google Scholar 

  29. Cho KS, Yang L, Lu B, Feng Ma H, Huang X, Pekny M, et al. Re-establishing the regenerative potential of central nervous system axons in postnatal mice. J Cell Sci. 2005;118(Pt 5):863–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lodovichi C, Di Cristo G, Cenni MC, Maffei L. Bcl-2 overexpression per se does not promote regeneration of neonatal crushed optic fibers. Eur J Neurosci. 2001;13(4):833–8.

    Article  CAS  PubMed  Google Scholar 

  31. Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, et al. Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron. 1994;13(4):1017–30.

    Article  CAS  PubMed  Google Scholar 

  32. Blackmore MG, Wang Z, Lerch JK, Motti D, Zhang YP, Shields CB, et al. Kruppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract. Proc Natl Acad Sci U S A. 2012;109(19):7517–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moore DL, Blackmore MG, Hu Y, Kaestner KH, Bixby JL, Lemmon VP, et al. KLF family members regulate intrinsic axon regeneration ability. Science. 2009;326(5950):298–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cai D, Qiu J, Cao Z, McAtee M, Bregman BS, Filbin MT. Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J Neurosci. 2001;21(13):4731–9.

    CAS  PubMed  Google Scholar 

  35. Qiu J, Cai D, Dai H, McAtee M, Hoffman PN, Bregman BS, et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron. 2002;34(6):895–903.

    Article  CAS  PubMed  Google Scholar 

  36. 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(9):1075–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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(5903):963–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Veldman MB, Bemben MA, Thompson RC, Goldman D. Gene expression analysis of zebrafish retinal ganglion cells during optic nerve regeneration identifies KLF6a and KLF7a as important regulators of axon regeneration. Dev Biol. 2007;312(2):596–612.

    Article  CAS  PubMed  Google Scholar 

  39. Meyer-Franke A, Kaplan MR, Pfrieger FW, Barres BA. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron. 1995;15(4):805–19.

    Article  CAS  PubMed  Google Scholar 

  40. Meyer-Franke A, Wilkinson GA, Kruttgen A, Hu M, Munro E, Hanson Jr MG, et al. Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron. 1998;21(4):681–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Glebova NO, Ginty DD. Growth and survival signals controlling sympathetic nervous system development. Annu Rev Neurosci. 2005;28:191–222.

    Article  CAS  PubMed  Google Scholar 

  42. Goldberg JL, Barres BA. The relationship between neuronal survival and regeneration. Annu Rev Neurosci. 2000;23:579–612.

    Article  CAS  PubMed  Google Scholar 

  43. Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond Ser B Biol Sci. 2006;361(1473):1545–64.

    Article  CAS  Google Scholar 

  44. Segal RA, Greenberg ME. Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci. 1996;19:463–89.

    Article  CAS  PubMed  Google Scholar 

  45. Zhou FQ, Snider WD. Intracellular control of developmental and regenerative axon growth. Philos Trans R Soc Lond Ser B Biol Sci. 2006;361(1473):1575–92.

    Article  CAS  Google Scholar 

  46. Cui Q, Yip HK, Zhao RC, So KF, Harvey AR. Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons. Mol Cell Neurosci. 2003;22(1):49–61.

    Article  CAS  PubMed  Google Scholar 

  47. Monsul NT, Geisendorfer AR, Han PJ, Banik R, Pease ME, Skolasky Jr RL, et al. Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve. Exp Neurol. 2004;186(2):124–33.

    Article  CAS  PubMed  Google Scholar 

  48. Gao Y, Deng K, Hou J, Bryson JB, Barco A, Nikulina E, et al. Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron. 2004;44(4):609–21.

    Article  CAS  PubMed  Google Scholar 

  49. Lu P, Yang H, Jones LL, Filbin MT, Tuszynski MH. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J Neurosci. 2004;24(28):6402–9.

    Article  CAS  PubMed  Google Scholar 

  50. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012;150(6):1264–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lu P, Woodruff G, Wang Y, Graham L, Hunt M, Wu D, et al. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron. 2014;83(4):789–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bradke F, Fawcett JW, Spira ME. Assembly of a new growth cone after axotomy: the precursor to axon regeneration. Nat Rev Neurosci. 2012;13(3):183–93.

    CAS  PubMed  Google Scholar 

  54. Lu Y, Belin S, He Z. Signaling regulations of neuronal regenerative ability. Curr Opin Neurobiol. 2014;27:135–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Watkins TA, Wang B, Huntwork-Rodriguez S, Yang J, Jiang Z, Eastham-Anderson J, et al. DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. Proc Natl Acad Sci U S A. 2013;110(10):4039–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yan D, Wu Z, Chisholm AD, Jin Y. The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell. 2009;138(5):1005–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Neumann S, Woolf CJ. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron. 1999;23(1):83–91.

    Article  CAS  PubMed  Google Scholar 

  58. Richardson PM, Issa VM. Peripheral injury enhances central regeneration of primary sensory neurones. Nature. 1984;309(5971):791–3.

    Article  CAS  PubMed  Google Scholar 

  59. Cao Z, Gao Y, Bryson JB, Hou J, Chaudhry N, Siddiq M, et al. The cytokine interleukin-6 is sufficient but not necessary to mimic the peripheral conditioning lesion effect on axonal growth. J Neurosci. 2006;26(20):5565–73.

    Article  CAS  PubMed  Google Scholar 

  60. Sendtner M, Stockli KA, Thoenen H. Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration. J Cell Biol. 1992;118(1):139–48.

    Article  CAS  PubMed  Google Scholar 

  61. Rishal I, Fainzilber M. Retrograde signaling in axonal regeneration. Exp Neurol. 2010;223(1):5–10.

    Article  CAS  PubMed  Google Scholar 

  62. 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(5):617–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hoffman PN. A conditioning lesion induces changes in gene expression and axonal transport that enhance regeneration by increasing the intrinsic growth state of axons. Exp Neurol. 2010;223(1):11–8.

    Article  CAS  PubMed  Google Scholar 

  64. Okano H, Yamanaka S. iPS cell technologies: significance and applications to CNS regeneration and disease. Mol Brain. 2014;7:22.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Okita K, Yamanaka S. Induced pluripotent stem cells: opportunities and challenges. Philos Trans R Soc Lond Ser B Biol Sci. 2011;366(1575):2198–207.

    Article  CAS  Google Scholar 

  66. Thoenen H, Sendtner M. Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nat Neurosci. 2002;5:1046–50.

    Article  CAS  PubMed  Google Scholar 

  67. Hannila SS, Filbin MT. The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury. Exp Neurol. 2008;209(2):321–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lewandowski G, Steward O. AAVshRNA-mediated suppression of PTEN in adult rats in combination with salmon fibrin administration enables regenerative growth of corticospinal axons and enhances recovery of voluntary motor function after cervical spinal cord injury. J Neurosci. 2014;34(30):9951–62.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Zukor K, Belin S, Wang C, Keelan N, Wang X, He Z. Short hairpin RNA against PTEN enhances regenerative growth of corticospinal tract axons after spinal cord injury. J Neurosci. 2013;33(39):15350–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sun F, Park KK, Belin S, Wang D, Lu T, Chen G, et al. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature. 2011;480(7377):372–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yin Y, Shen WH. PTEN: a new guardian of the genome. Oncogene. 2008;27(41):5443–53.

    Article  CAS  PubMed  Google Scholar 

  72. Kazanecki CC, Uzwiak DJ, Denhardt DT. Control of osteopontin signaling and function by post-translational phosphorylation and protein folding. J Cell Biochem. 2007;102(4):912–24.

    Article  CAS  PubMed  Google Scholar 

  73. Duan X, Qiao M, Bei F, Kim IJ, He Z, Sanes JR. Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron. 2015;85(6):1244–56.

    Article  CAS  PubMed  Google Scholar 

  74. Baker BJ, Akhtar LN, Benveniste EN. SOCS1 and SOCS3 in the control of CNS immunity. Trends Immunol. 2009;30(8):392–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Croker BA, Kiu H, Nicholson SE. SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol. 2008;19(4):414–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Berry M, Carlile J, Hunter A. Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. J Neurocytol. 1996;25(2):147–70.

    Article  CAS  PubMed  Google Scholar 

  77. Fischer D, Heiduschka P, Thanos S. Lens-injury-stimulated axonal regeneration throughout the optic pathway of adult rats. Exp Neurol. 2001;172(2):257–72.

    Article  CAS  PubMed  Google Scholar 

  78. Kurimoto T, Yin Y, Habboub G, Gilbert HY, Li Y, Nakao S, et al. Neutrophils express oncomodulin and promote optic nerve regeneration. J Neurosci. 2013;33(37):14816–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Leon S, Yin Y, Nguyen J, Irwin N, Benowitz LI. Lens injury stimulates axon regeneration in the mature rat optic nerve. J Neurosci. 2000;20(12):4615–26.

    CAS  PubMed  Google Scholar 

  80. Benowitz LI, Popovich PG. Inflammation and axon regeneration. Curr Opin Neurol. 2011;24(6):577–83.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Zhigang He PhD .

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Bei, F., He, Z. (2016). Intrinsic Neuronal Mechanisms in Axon Regeneration After Spinal Cord Injury. In: Tuszynski, M. (eds) Translational Neuroscience. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-7654-3_21

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