1932

Abstract

After an injury in the adult mammalian central nervous system (CNS), lesioned axons fail to regenerate. This failure to regenerate contrasts with axons’ remarkable potential to grow during embryonic development and after an injury in the peripheral nervous system (PNS). Several intracellular mechanisms—including cytoskeletal dynamics, axonal transport and trafficking, signaling and transcription of regenerative programs, and epigenetic modifications—control axon regeneration. In this review, we describe how manipulation of intrinsic mechanisms elicits a regenerative response in different organisms and how strategies are implemented to form the basis of a future regenerative treatment after CNS injury.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cellbio-100617-062508
2018-10-06
2024-10-10
Loading full text...

Full text loading...

/deliver/fulltext/cellbio/34/1/annurev-cellbio-100617-062508.html?itemId=/content/journals/10.1146/annurev-cellbio-100617-062508&mimeType=html&fmt=ahah

Literature Cited

  1. Aktories K, Wilde C, Vogelsgesang M 2004. Rho-modifying C3-like ADP-ribosyltransferases. Rev. Physiol. Biochem. Pharmacol. 152:1–22
    [Google Scholar]
  2. Al-Ali H, Ding Y, Slepak T, Wu W, Sun Y et al. 2017. The mTOR substrate S6 kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for central nervous system injury. J. Neurosci. 37:7079–95
    [Google Scholar]
  3. Anderson MA, Burda JE, Ren Y, Ao Y, O'Shea TM et al. 2016. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195–200
    [Google Scholar]
  4. Apara A, Galvao J, Wang Y, Blackmore M, Trillo A et al. 2017. KLF9 and JNK3 interact to suppress axon regeneration in the adult CNS. J. Neurosci. 37:9632–44
    [Google Scholar]
  5. Ashery U, Penner R, Spira ME 1996. Acceleration of membrane recycling by axotomy of cultured Aplysia neurons. Neuron 16:641–51
    [Google Scholar]
  6. Ayaz D, Leyssen M, Koch M, Yan J, Srahna M et al. 2008. Axonal injury and regeneration in the adult brain of Drosophila. J. . Neurosci 28:6010–21
    [Google Scholar]
  7. Bareyre FM, Garzorz N, Lang C, Misgeld T, Buning H, Kerschensteiner M 2011. In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration. PNAS 108:6282–87
    [Google Scholar]
  8. Becker T, Wullimann MF, Becker CG, Bernhardt RR, Schachner M 1997. Axonal regrowth after spinal cord transection in adult zebrafish. J. Comp. Neurol. 377:577–95
    [Google Scholar]
  9. Bei F, Lee HHC, Liu X, Gunner G, Jin H et al. 2016. Restoration of visual function by enhancing conduction in regenerated axons. Cell 164:219–32
    [Google Scholar]
  10. Belin S, Nawabi H, Wang C, Tang S, Latremoliere A et al. 2015. Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics. Neuron 86:1000–14
    [Google Scholar]
  11. Blackmore MG, Wang Z, Lerch JK, Motti D, Zhang YP et al. 2012. Krüppel-like factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract. PNAS 109:7517–22
    [Google Scholar]
  12. Blesch A, Lu P, Tsukada S, Alto LT, Roet K et al. 2012. Conditioning lesions before or after spinal cord injury recruit broad genetic mechanisms that sustain axonal regeneration: superiority to camp-mediated effects. Exp. Neurol. 235:162–73
    [Google Scholar]
  13. Brace EJ, DiAntonio A 2017. Models of axon regeneration in Drosophila. Exp. Neurol 287:310–17
    [Google Scholar]
  14. Bradke F, Dotti CG 1999. The role of local actin instability in axon formation. Science 283:1931–34
    [Google Scholar]
  15. Bradke F, Fawcett JW, Spira ME 2012. Assembly of a new growth cone after axotomy: the precursor to axon regeneration. Nat. Rev. Neurosci. 13:183–93
    [Google Scholar]
  16. Bray ER, Noga M, Thakor K, Wang Y, Lemmon VP et al. 2017. 3D visualization of individual regenerating retinal ganglion cell axons reveals surprisingly complex growth paths. eNeuro 4:e0093–17.201
    [Google Scholar]
  17. Brosius Lutz A, Barres BA 2014. Contrasting the glial response to axon injury in the central and peripheral nervous systems. Dev. Cell 28:7–17
    [Google Scholar]
  18. Byrne AB, Hammarlund M 2017. Axon regeneration in C. elegans: worming our way to mechanisms of axon regeneration. Exp. Neurol. 287:300–9
    [Google Scholar]
  19. Byrne AB, Walradt T, Gardner KE, Hubbert A, Reinke V, Hammarlund M 2014. Insulin/IGF1 signaling inhibits age-dependent axon regeneration. Neuron 81:561–73
    [Google Scholar]
  20. Cartoni R, Norsworthy MW, Bei F, Wang C, Li S et al. 2016. The mammalian-specific protein Armcx1 regulates mitochondrial transport during axon regeneration. Neuron 92:1294–307
    [Google Scholar]
  21. Chen L, Wang Z, Ghosh-Roy A, Hubert T, Yan D et al. 2011. Axon regeneration pathways identified by systematic genetic screening in C. elegans. . Neuron 71:1043–57
    [Google Scholar]
  22. Chen Y, Sheng ZH 2013. Kinesin-1–syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport. J. Cell Biol. 202:351–64
    [Google Scholar]
  23. Chierzi S, Ratto GM, Verma P, Fawcett JW 2005. The ability of axons to regenerate their growth cones depends on axonal type and age, and is regulated by calcium, cAMP and ERK. Eur. J. Neurosci. 21:2051–62
    [Google Scholar]
  24. Cho Y, Cavalli V 2012. HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration. EMBO J 31:3063–78
    [Google Scholar]
  25. Cho Y, Cavalli V 2014. HDAC signaling in neuronal development and axon regeneration. Curr. Opin. Neurobiol. 27:118–26
    [Google Scholar]
  26. Cho Y, Sloutsky R, Naegle KM, Cavalli V 2013. Injury-induced HDAC5 nuclear export is essential for axon regeneration. Cell 155:894–908
    [Google Scholar]
  27. Christie KJ, Webber CA, Martinez JA, Singh B, Zochodne DW 2010. PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. J. Neurosci. 30:9306–15
    [Google Scholar]
  28. Coles CH, Bradke F 2015. Coordinating neuronal actin-microtubule dynamics. Curr. Biol. 25:R677–91
    [Google Scholar]
  29. David S, Aguayo AJ 1981. Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214:931–33
    [Google Scholar]
  30. Dergham P, Ellezam B, Essagian C, Avedissian H, Lubell WD, McKerracher L 2002. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22:6570–77
    [Google Scholar]
  31. Du K, Zheng S, Zhang Q, Li S, Gao X et al. 2015. Pten deletion promotes regrowth of corticospinal tract axons 1 year after spinal cord injury. J. Neurosci. 35:9754–63
    [Google Scholar]
  32. Duan X, Qiao M, Bei F, Kim IJ, He Z, Sanes JR 2015. Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron 85:1244–56
    [Google Scholar]
  33. Enes J, Langwieser N, Ruschel J, Carballosa-Gonzalez MM, Klug A et al. 2010. Electrical activity suppresses axon growth through CaV1.2 channels in adult primary sensory neurons. Curr. Biol. 20:1154–64
    [Google Scholar]
  34. Erck C, Peris L, Andrieux A, Meissirel C, Gruber AD et al. 2005. A vital role of tubulin-tyrosine-ligase for neuronal organization. PNAS 102:7853–58
    [Google Scholar]
  35. Erez H, Malkinson G, Prager-Khoutorsky M, De Zeeuw CI, Hoogenraad CC, Spira ME 2007. Formation of microtubule-based traps controls the sorting and concentration of vesicles to restricted sites of regenerating neurons after axotomy. J. Cell Biol. 176:497–507
    [Google Scholar]
  36. Erturk A, Hellal F, Enes J, Bradke F 2007. Disorganized microtubules underlie the formation of retraction bulbs and the failure of axonal regeneration. J. Neurosci. 27:9169–80
    [Google Scholar]
  37. Erturk A, Mauch CP, Hellal F, Forstner F, Keck T et al. 2011. Three-dimensional imaging of the unsectioned adult spinal cord to assess axon regeneration and glial responses after injury. Nat. Med. 18:166–71
    [Google Scholar]
  38. Eva R, Koseki H, Kanamarlapudi V, Fawcett JW 2017. EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment. J. Cell Sci. 130:3663–75
    [Google Scholar]
  39. Fehlings MG, Theodore N, Harrop J, Maurais G, Kuntz C et al. 2011. A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J. Neurotrauma 28:787–96
    [Google Scholar]
  40. Finelli MJ, Wong JK, Zou H 2013. Epigenetic regulation of sensory axon regeneration after spinal cord injury. J. Neurosci. 33:19664–76
    [Google Scholar]
  41. Flynn KC, Hellal F, Neukirchen D, Jacob S, Tahirovic S et al. 2012. ADF/cofilin-mediated actin retrograde flow directs neurite formation in the developing brain. Neuron 76:1091–107
    [Google Scholar]
  42. Garvalov BK, Flynn KC, Neukirchen D, Meyn L, Teusch N et al. 2007. Cdc42 regulates cofilin during the establishment of neuronal polarity. J. Neurosci. 27:13117–29
    [Google Scholar]
  43. Gaub P, Joshi Y, Wuttke A, Naumann U, Schnichels S et al. 2011. The histone acetyltransferase p300 promotes intrinsic axonal regeneration. Brain 134:2134–48
    [Google Scholar]
  44. Gaub P, Tedeschi A, Puttagunta R, Nguyen T, Schmandke A, Di Giovanni S 2010. HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation. Cell Death Differ 17:1392–408
    [Google Scholar]
  45. Geoffroy CG, Hilton BJ, Tetzlaff W, Zheng B 2016. Evidence for an age-dependent decline in axon regeneration in the adult mammalian central nervous system. Cell Rep 15:238–46
    [Google Scholar]
  46. Ghosh-Roy A, Wu Z, Goncharov A, Jin Y, Chisholm AD 2010. Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase. J. Neurosci. 30:3175–83
    [Google Scholar]
  47. Gitler D, Spira ME 1998. Real time imaging of calcium-induced localized proteolytic activity after axotomy and its relation to growth cone formation. Neuron 20:1123–35
    [Google Scholar]
  48. Gobrecht P, Andreadaki A, Diekmann H, Heskamp A, Leibinger M, Fischer D 2016. Promotion of functional nerve regeneration by inhibition of microtubule detyrosination. J. Neurosci. 36:3890–902
    [Google Scholar]
  49. Gobrecht P, Leibinger M, Andreadaki A, Fischer D 2014. Sustained GSK3 activity markedly facilitates nerve regeneration. Nat. Commun. 5:4561
    [Google Scholar]
  50. Godell CM, Smyers ME, Eddleman CS, Ballinger ML, Fishman HM, Bittner GD 1997. Calpain activity promotes the sealing of severed giant axons. PNAS 94:4751–56
    [Google Scholar]
  51. Goldberg JL, Klassen MP, Hua Y, Barres BA 2002. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 296:1860–64
    [Google Scholar]
  52. Gomis-Ruth S, Wierenga CJ, Bradke F 2008. Plasticity of polarization: changing dendrites into axons in neurons integrated in neuronal circuits. Curr. Biol. 18:992–1000
    [Google Scholar]
  53. Graciarena M, Dambly-Chaudiere C, Ghysen A 2014. Dynamics of axonal regeneration in adult and aging zebrafish reveal the promoting effect of a first lesion. PNAS 111:1610–15
    [Google Scholar]
  54. Guo X, Snider WD, Chen B 2016. GSK3β regulates AKT-induced central nervous system axon regeneration via an eIF2Bε-dependent, mTORC1-independent pathway. eLife 5:e11903
    [Google Scholar]
  55. Hammarlund M, Jin Y 2014. Axon regeneration in C. elegans. Curr. Opin. . Neurobiol 27:199–207
    [Google Scholar]
  56. Hammarlund M, Nix P, Hauth L, Jorgensen EM, Bastiani M 2009. Axon regeneration requires a conserved MAP kinase pathway. Science 323:802–6
    [Google Scholar]
  57. Han SM, Baig HS, Hammarlund M 2016. Mitochondria localize to injured axons to support regeneration. Neuron 92:1308–23
    [Google Scholar]
  58. Hao Y, Collins C 2017. Intrinsic mechanisms for axon regeneration: insights from injured axons in Drosophila. Curr. Opin. Genet. . Dev 44:84–91
    [Google Scholar]
  59. Hellal F, Hurtado A, Ruschel J, Flynn KC, Laskowski CJ et al. 2011. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331:928–31
    [Google Scholar]
  60. Hilton BJ, Bradke F 2017. Can injured adult CNS axons regenerate by recapitulating development?. Development 144:3417–29
    [Google Scholar]
  61. Hoffman PN 2010. A conditioning lesion induces changes in gene expression and axonal transport that enhance regeneration by increasing the intrinsic growth state of axons. Exp. Neurol. 223:11–18
    [Google Scholar]
  62. Howard MJ, David G, Barrett JN 1999. Resealing of transected myelinated mammalian axons in vivo: evidence for involvement of calpain. Neuroscience 93:807–15
    [Google Scholar]
  63. Inagaki N, Chihara K, Arimura N, Menager C, Kawano Y et al. 2001. CRMP-2 induces axons in cultured hippocampal neurons. Nat. Neurosci. 4:781–82
    [Google Scholar]
  64. Jankowski MP, McIlwrath SL, Jing X, Cornuet PK, Salerno KM et al. 2009. Sox11 transcription factor modulates peripheral nerve regeneration in adult mice. Brain Res 1256:43–54
    [Google Scholar]
  65. Jin D, Liu Y, Sun F, Wang X, Liu X, He Z 2015. Restoration of skilled locomotion by sprouting corticospinal axons induced by co-deletion of PTEN and SOCS3. Nat. Commun. 6:8074
    [Google Scholar]
  66. Jing X, Wang T, Huang S, Glorioso JC, Albers KM 2012. The transcription factor Sox11 promotes nerve regeneration through activation of the regeneration-associated gene Sprr1a. Exp. . Neurol 233:221–32
    [Google Scholar]
  67. Joset A, Dodd DA, Halegoua S, Schwab ME 2010. Pincher-generated Nogo-A endosomes mediate growth cone collapse and retrograde signaling. J. Cell Biol. 188:271–85
    [Google Scholar]
  68. Kamber D, Erez H, Spira ME 2009. Local calcium-dependent mechanisms determine whether a cut axonal end assembles a retarded endbulb or competent growth cone. Exp. Neurol. 219:112–25
    [Google Scholar]
  69. Kang JS, Tian JH, Pan PY, Zald P, Li C et al. 2008. Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell 132:137–48
    [Google Scholar]
  70. Kerschensteiner M, Schwab ME, Lichtman JW, Misgeld T 2005. In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nat. Med. 11:572–77
    [Google Scholar]
  71. Knoferle J, Koch JC, Ostendorf T, Michel U, Planchamp V et al. 2010. Mechanisms of acute axonal degeneration in the optic nerve in vivo. PNAS 107:6064–69
    [Google Scholar]
  72. Koseki H, Donega M, Lam BY, Petrova V, van Erp S et al. 2017. Selective rab11 transport and the intrinsic regenerative ability of CNS axons. eLife 6:e26956
    [Google Scholar]
  73. Krause TL, Fishman HM, Ballinger ML, Bittner GD 1994. Extent and mechanism of sealing in transected giant axons of squid and earthworms. J. Neurosci. 14:6638–51
    [Google Scholar]
  74. Kulbatski I, Cook DJ, Tator CH 2004. Calcium entry through L-type calcium channels is essential for neurite regeneration in cultured sympathetic neurons. J. Neurotrauma 21:357–74
    [Google Scholar]
  75. Lehmann M, Fournier A, Selles-Navarro I, Dergham P, Sebok A et al. 1999. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19:7537–47
    [Google Scholar]
  76. Leibinger M, Andreadaki A, Golla R, Levin E, Hilla AM et al. 2017. Boosting CNS axon regeneration by harnessing antagonistic effects of GSK3 activity. PNAS 114:E5454–63
    [Google Scholar]
  77. Leon S, Yin Y, Nguyen J, Irwin N, Benowitz LI 2000. Lens injury stimulates axon regeneration in the mature rat optic nerve. J. Neurosci. 20:4615–26
    [Google Scholar]
  78. Lim JH, Stafford BK, Nguyen PL, Lien BV, Wang C et al. 2016. Neural activity promotes long-distance, target-specific regeneration of adult retinal axons. Nat. Neurosci. 19:1073–84
    [Google Scholar]
  79. Liu D, Yu Y, Schachner M 2014. Ptena, but not Ptenb, reduces regeneration after spinal cord injury in adult zebrafish. Exp. Neurol. 261:196–205
    [Google Scholar]
  80. Liu K, Lu Y, Lee JK, Samara R, Willenberg R et al. 2010. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13:1075–81
    [Google Scholar]
  81. Liu K, Tedeschi A, Park KK, He Z 2011. Neuronal intrinsic mechanisms of axon regeneration. Annu. Rev. Neurosci. 34:131–52
    [Google Scholar]
  82. Liu RY, Snider WD 2001. Different signaling pathways mediate regenerative versus developmental sensory axon growth. J. Neurosci. 21:RC164
    [Google Scholar]
  83. Liu Y, Wang X, Li W, Zhang Q, Li Y et al. 2017. A sensitized IGF1 treatment restores corticospinal axon-dependent functions. Neuron 95:817–33.e4
    [Google Scholar]
  84. Liz MA, Mar FM, Santos TE, Pimentel HI, Marques AM et al. 2014. Neuronal deletion of GSK3β increases microtubule speed in the growth cone and enhances axon regeneration via CRMP-2 and independently of MAP1B and CLASP2. BMC Biol 12:47
    [Google Scholar]
  85. Loh YE, Koemeter-Cox A, Finelli MJ, Shen L, Friedel RH, Zou H 2017. Comprehensive mapping of 5-hydroxymethylcytosine epigenetic dynamics in axon regeneration. Epigenetics 12:77–92
    [Google Scholar]
  86. López-Doménech G, Serrat R, Mirra S, D'Aniello S, Somorjai I et al. 2012. The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2. Nat. Commun. 3:814
    [Google Scholar]
  87. Lorenzana AO, Lee JK, Mui M, Chang A, Zheng B 2015. A surviving intact branch stabilizes remaining axon architecture after injury as revealed by in vivo imaging in the mouse spinal cord. Neuron 86:947–54
    [Google Scholar]
  88. Maday S, Twelvetrees AE, Moughamian AJ, Holzbaur EL 2014. Axonal transport: cargo-specific mechanisms of motility and regulation. Neuron 84:292–309
    [Google Scholar]
  89. Mandolesi G, Madeddu F, Bozzi Y, Maffei L, Ratto GM 2004. Acute physiological response of mammalian central neurons to axotomy: ionic regulation and electrical activity. FASEB J 18:1934–36
    [Google Scholar]
  90. Mansour-Robaey S, Clarke DB, Wang YC, Bray GM, Aguayo AJ 1994. Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. PNAS 91:1632–36
    [Google Scholar]
  91. Mar FM, Simoes AR, Leite S, Morgado MM, Santos TE et al. 2014. CNS axons globally increase axonal transport after peripheral conditioning. J. Neurosci. 34:5965–70
    [Google Scholar]
  92. Mehta ST, Luo X, Park KK, Bixby JL, Lemmon VP 2016. Hyperactivated Stat3 boosts axon regeneration in the CNS. Exp. Neurol. 280:115–20
    [Google Scholar]
  93. Miao T, Wu D, Zhang Y, Bo X, Subang MC et al. 2006. Suppressor of cytokine signaling-3 suppresses the ability of activated signal transducer and activator of transcription-3 to stimulate neurite growth in rat primary sensory neurons. J. Neurosci. 26:9512–19
    [Google Scholar]
  94. Mimura F, Yamagishi S, Arimura N, Fujitani M, Kubo T et al. 2006. Myelin-associated glycoprotein inhibits microtubule assembly by a Rho-kinase-dependent mechanism. J. Biol. Chem. 281:15970–79
    [Google Scholar]
  95. Monnier PP, Sierra A, Schwab JM, Henke-Fahle S, Mueller BK 2003. The Rho/ROCK pathway mediates neurite growth–inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar. Mol. Cell. Neurosci. 22:319–30
    [Google Scholar]
  96. Moore DL, Blackmore MG, Hu Y, Kaestner KH, Bixby JL et al. 2009. KLF family members regulate intrinsic axon regeneration ability. Science 326:298–301
    [Google Scholar]
  97. Moore DL, Goldberg JL 2011. Multiple transcription factor families regulate axon growth and regeneration. Dev. Neurobiol. 71:1186–211
    [Google Scholar]
  98. Nawabi H, Belin S, Cartoni R, Williams PR, Wang C et al. 2015. Doublecortin-like kinases promote neuronal survival and induce growth cone reformation via distinct mechanisms. Neuron 88:704–19
    [Google Scholar]
  99. Neumann B, Coakley S, Giordano-Santini R, Linton C, Lee ES et al. 2015. EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature 517:219–22
    [Google Scholar]
  100. Neumann S, Bradke F, Tessier-Lavigne M, Basbaum AI 2002. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron 34:885–93
    [Google Scholar]
  101. Neumann S, Woolf CJ 1999. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron 23:83–91
    [Google Scholar]
  102. Norsworthy MW, Bei F, Kawaguchi R, Wang Q, Tran NM et al. 2017. Sox11 expression promotes regeneration of some retinal ganglion cell types but kills others. Neuron 94:1112–20.e4
    [Google Scholar]
  103. Omura T, Omura K, Tedeschi A, Riva P, Painter MW et al. 2015. Robust axonal regeneration occurs in the injured CAST/Ei mouse CNS. Neuron 86:1215–27
    [Google Scholar]
  104. Pan C, Cai R, Quacquarelli FP, Ghasemigharagoz A, Lourbopoulos A et al. 2016. Shrinkage-mediated imaging of entire organs and organisms using uDISCO. Nat. Methods 13:859–67
    [Google Scholar]
  105. Pap M, Cooper GM 2002. Role of translation initiation factor 2B in control of cell survival by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3β signaling pathway. Mol. Cell. Biol. 22:578–86
    [Google Scholar]
  106. Park KK, Liu K, Hu Y, Smith PD, Wang C et al. 2008. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322:963–66
    [Google Scholar]
  107. Polleux F, Snider W 2010. Initiating and growing an axon. Cold Spring Harb. Perspect. Biol. 2:a001925
    [Google Scholar]
  108. Puttagunta R, Tedeschi A, Soria MG, Hervera A, Lindner R et al. 2014. PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system. Nat. Commun. 5:3527
    [Google Scholar]
  109. Qin S, Zou Y, Zhang CL 2013. Cross-talk between KLF4 and STAT3 regulates axon regeneration. Nat. Commun. 4:2633
    [Google Scholar]
  110. Qiu J, Cai D, Dai H, McAtee M, Hoffman PN et al. 2002. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34:895–903
    [Google Scholar]
  111. Rasmussen JP, Sagasti A 2017. Learning to swim, again: axon regeneration in fish. Exp. Neurol. 287:318–30
    [Google Scholar]
  112. Rawlings JS, Rosler KM, Harrison DA 2004. The JAK/STAT signaling pathway. J. Cell Sci. 117:1281–83
    [Google Scholar]
  113. Renier N, Wu Z, Simon DJ, Yang J, Ariel P, Tessier-Lavigne M 2014. iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging. Cell 159:896–910
    [Google Scholar]
  114. Richardson PM, Issa VM 1984. Peripheral injury enhances central regeneration of primary sensory neurones. Nature 309:791–93
    [Google Scholar]
  115. Richardson PM, McGuinness UM, Aguayo AJ 1980. Axons from CNS neurons regenerate into PNS grafts. Nature 284:264–65
    [Google Scholar]
  116. Rishal I, Fainzilber M 2014. Axon-soma communication in neuronal injury. Nat. Rev. Neurosci. 15:32–42
    [Google Scholar]
  117. Ruschel J, Bradke F 2018. Systemic administration of epothilone D improves functional recovery of walking after rat spinal cord contusion injury. Exp. Neurol. 306:243–49
    [Google Scholar]
  118. Ruschel J, Hellal F, Flynn KC, Dupraz S, Elliott DA et al. 2015. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury. Science 348:347–52
    [Google Scholar]
  119. Saijilafu, Hur EM, Liu CM, Jiao Z, Xu WL, Zhou FQ 2013. PI3K-GSK3 signalling regulates mammalian axon regeneration by inducing the expression of Smad1. Nat. Commun. 4:2690
    [Google Scholar]
  120. Schwab ME, Kapfhammer JP, Bandtlow CE 1993. Inhibitors of neurite growth. Annu. Rev. Neurosci. 16:565–95
    [Google Scholar]
  121. Schwab ME, Strittmatter SM 2014. Nogo limits neural plasticity and recovery from injury. Curr. Opin. Neurobiol. 27:53–60
    [Google Scholar]
  122. Schwarz TL 2013. Mitochondrial trafficking in neurons. Cold Spring Harb. Perspect. Biol. 5:a011304
    [Google Scholar]
  123. Sengottuvel V, Leibinger M, Pfreimer M, Andreadaki A, Fischer D 2011. Taxol facilitates axon regeneration in the mature CNS. J. Neurosci. 31:2688–99
    [Google Scholar]
  124. Sheng ZH 2017. The interplay of axonal energy homeostasis and mitochondrial trafficking and anchoring. Trends Cell Biol 27:403–16
    [Google Scholar]
  125. Shin JE, Cho Y, Beirowski B, Milbrandt J, Cavalli V, DiAntonio A 2012. Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron 74:1015–22
    [Google Scholar]
  126. Silver J, Schwab ME, Popovich PG 2014. Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb. Perspect. Biol. 7:a020602
    [Google Scholar]
  127. Smith DS, Skene JH 1997. A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth. J. Neurosci. 17:646–58
    [Google Scholar]
  128. Smith PD, Sun F, Park KK, Cai B, Wang C et al. 2009. SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron 64:617–23
    [Google Scholar]
  129. Song MS, Salmena L, Pandolfi PP 2012. The functions and regulation of the PTEN tumour suppressor. Nat. Rev. Mol. Cell Biol. 13:283–96
    [Google Scholar]
  130. Song W, Cho Y, Watt D, Cavalli V 2015. Tubulin-tyrosine ligase (TTL)-mediated increase in tyrosinated α-tubulin in injured axons is required for retrograde injury signaling and axon regeneration. J. Biol. Chem. 290:14765–75
    [Google Scholar]
  131. Song Y, Brady ST 2015. Post-translational modifications of tubulin: pathways to functional diversity of microtubules. Trends Cell Biol 25:125–36
    [Google Scholar]
  132. Song Y, Ori-McKenney KM, Zheng Y, Han C, Jan LY, Jan YN 2012. Regeneration of Drosophila sensory neuron axons and dendrites is regulated by the Akt pathway involving Pten and microRNA bantam. . Genes Dev 26:1612–25
    [Google Scholar]
  133. Song Y, Sretavan D, Salegio EA, Berg J, Huang X et al. 2015. Regulation of axon regeneration by the RNA repair and splicing pathway. Nat. Neurosci. 18:817–25
    [Google Scholar]
  134. Spira ME, Benbassat D, Dormann A 1993. Resealing of the proximal and distal cut ends of transected axons: electrophysiological and ultrastructural analysis. J. Neurobiol. 24:300–16
    [Google Scholar]
  135. Stone MC, Nguyen MM, Tao J, Allender DL, Rolls MM 2010. Global up-regulation of microtubule dynamics and polarity reversal during regeneration of an axon from a dendrite. Mol. Biol. Cell 21:767–77
    [Google Scholar]
  136. Sun F, Park KK, Belin S, Wang D, Lu T et al. 2011. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 480:372–75
    [Google Scholar]
  137. Sun W, Smith D, Fu Y, Cheng JX, Bryn S et al. 2010. Novel potassium channel blocker, 4-AP-3-MeOH, inhibits fast potassium channels and restores axonal conduction in injured guinea pig spinal cord white matter. J. Neurophysiol. 103:469–78
    [Google Scholar]
  138. Tahirovic S, Bradke F 2009. Neuronal polarity. Cold Spring Harb. Perspect. Biol. 1:a001644
    [Google Scholar]
  139. Tahirovic S, Hellal F, Neukirchen D, Hindges R, Garvalov BK et al. 2010. Rac1 regulates neuronal polarization through the WAVE complex. J. Neurosci. 30:6930–43
    [Google Scholar]
  140. Tanabe K, Bonilla I, Winkles JA, Strittmatter SM 2003. Fibroblast growth factor-inducible-14 is induced in axotomized neurons and promotes neurite outgrowth. J. Neurosci. 23:9675–86
    [Google Scholar]
  141. Tedeschi A 2011. Tuning the orchestra: transcriptional pathways controlling axon regeneration. Front. Mol. Neurosci. 4:60
    [Google Scholar]
  142. Tedeschi A, Bradke F 2013. The DLK signalling pathway—a double-edged sword in neural development and regeneration. EMBO Rep 14:605–14
    [Google Scholar]
  143. Tedeschi A, Dupraz S, Laskowski CJ, Xue J, Ulas T et al. 2016. The calcium channel subunit Alpha2delta2 suppresses axon regeneration in the adult CNS. Neuron 92:419–34
    [Google Scholar]
  144. Tedeschi A, Omura T, Costigan M 2017. CNS repair and axon regeneration: using genetic variation to determine mechanisms. Exp. Neurol. 287:409–22
    [Google Scholar]
  145. Tuszynski MH, Steward O 2012. Concepts and methods for the study of axonal regeneration in the CNS. Neuron 74:777–91
    [Google Scholar]
  146. Valakh V, Frey E, Babetto E, Walker LJ, DiAntonio A 2015. Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury. Neurobiol. Dis. 77:13–25
    [Google Scholar]
  147. van Battum EY, Verhagen MG, Vangoor VR, Fujita Y, Derijck A et al. 2018. An image-based miRNA screen identifies miRNA-135s as regulators of CNS axon growth and regeneration by targeting Krüppel-like factor 4. J. Neurosci. 38:613–30
    [Google Scholar]
  148. Verma P, Chierzi S, Codd AM, Campbell DS, Meyer RL et al. 2005. Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. J. Neurosci. 25:331–42
    [Google Scholar]
  149. Wang Z, Reynolds A, Kirry A, Nienhaus C, Blackmore MG 2015. Overexpression of Sox11 promotes corticospinal tract regeneration after spinal injury while interfering with functional recovery. J. Neurosci. 35:3139–45
    [Google Scholar]
  150. Warner FM, Cragg JJ, Jutzeler CR, Rohrich F, Weidner N et al. 2017. Early administration of gabapentinoids improves motor recovery after human spinal cord injury. Cell Rep 18:1614–18
    [Google Scholar]
  151. Watkins TA, Wang B, Huntwork-Rodriguez S, Yang J, Jiang Z et al. 2013. DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. PNAS 110:4039–44
    [Google Scholar]
  152. Welsbie DS, Mitchell KL, Jaskula-Ranga V, Sluch VM, Yang Z et al. 2017. Enhanced functional genomic screening identifies novel mediators of dual leucine zipper kinase–dependent injury signaling in neurons. Neuron 94:1142–54.e6
    [Google Scholar]
  153. Weng YL, An R, Cassin J, Joseph J, Mi R et al. 2017. An intrinsic epigenetic barrier for functional axon regeneration. Neuron 94:337–46.e6
    [Google Scholar]
  154. Williams PR, Marincu BN, Sorbara CD, Mahler CF, Schumacher AM et al. 2014. A recoverable state of axon injury persists for hours after spinal cord contusion in vivo. Nat. Commun. 5:5683
    [Google Scholar]
  155. Witte H, Bradke F 2008. The role of the cytoskeleton during neuronal polarization. Curr. Opin. Neurobiol. 18:479–87
    [Google Scholar]
  156. Witte H, Neukirchen D, Bradke F 2008. Microtubule stabilization specifies initial neuronal polarization. J. Cell Biol. 180:619–32
    [Google Scholar]
  157. Wu X, Zhang Y 2017. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 18:517–34
    [Google Scholar]
  158. Wu Z, Ghosh-Roy A, Yanik MF, Zhang JZ, Jin Y, Chisholm AD 2007. Caenorhabditis elegans neuronal regeneration is influenced by life stage, ephrin signaling, and synaptic branching. PNAS 104:15132–37
    [Google Scholar]
  159. Yan D, Jin Y 2012. Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform. Neuron 76:534–48
    [Google Scholar]
  160. Yan D, Wu Z, Chisholm AD, Jin Y 2009. The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell 138:1005–18
    [Google Scholar]
  161. Yanik MF, Cinar H, Cinar HN, Chisholm AD, Jin Y, Ben-Yakar A 2004. Neurosurgery: functional regeneration after laser axotomy. Nature 432:822
    [Google Scholar]
  162. Ylera B, Erturk A, Hellal F, Nadrigny F, Hurtado A et al. 2009. Chronically CNS-injured adult sensory neurons gain regenerative competence upon a lesion of their peripheral axon. Curr. Biol. 19:930–36
    [Google Scholar]
  163. Yoo S, Nguyen MP, Fukuda M, Bittner GD, Fishman HM 2003. Plasmalemmal sealing of transected mammalian neurites is a gradual process mediated by Ca2+-regulated proteins. J. Neurosci. Res. 74:541–51
    [Google Scholar]
  164. Zhang JN, Michel U, Lenz C, Friedel CC, Koster S et al. 2016. Calpain-mediated cleavage of collapsin response mediator protein-2 drives acute axonal degeneration. Sci. Rep. 6:37050
    [Google Scholar]
  165. Zhou B, Yu P, Lin MY, Sun T, Chen Y, Sheng ZH 2016. Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. J. Cell Biol. 214:103–19
    [Google Scholar]
  166. Zigmond RE 2011. gp130 cytokines are positive signals triggering changes in gene expression and axon outgrowth in peripheral neurons following injury. Front. Mol. Neurosci. 4:62
    [Google Scholar]
  167. Ziv NE, Spira ME 1993. Spatiotemporal distribution of Ca2+ following axotomy and throughout the recovery process of cultured Aplysia neurons. Eur. J. Neurosci. 5:657–68
    [Google Scholar]
  168. Ziv NE, Spira ME 1995. Axotomy induces a transient and localized elevation of the free intracellular calcium concentration to the millimolar range. J. Neurophysiol. 74:2625–37
    [Google Scholar]
  169. Zukor K, Belin S, Wang C, Keelan N, Wang X, He Z 2013. Short hairpin RNA against PTEN enhances regenerative growth of corticospinal tract axons after spinal cord injury. J. Neurosci. 33:15350–61
    [Google Scholar]
/content/journals/10.1146/annurev-cellbio-100617-062508
Loading
/content/journals/10.1146/annurev-cellbio-100617-062508
Loading

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error