Signaling pathways that regulate axon regeneration

Saijilafu; Bo-Yin Zhang; Feng-Quan Zhou

doi:10.1007/s12264-013-1357-4

. 2013 Jul 11;29(4):411–420. doi: 10.1007/s12264-013-1357-4

Signaling pathways that regulate axon regeneration

Saijilafu ¹¹³⁵⁷, Bo-Yin Zhang ¹¹³⁵⁷, Feng-Quan Zhou ^11357,^21357,^✉

PMCID: PMC5561939 PMID: 23846598

Abstract

Neurons in the mammalian central nervous system (CNS) cannot regenerate axons after injury. in contrast, neurons in the mammalian peripheral nervous system and in some non-mammalian models, such as C. elegans and Drosophila, are able to regrow axons. Understanding the molecular mechanisms by which these neurons support axon regeneration will help us find ways to enhance mammalian CNS axon regeneration. Here, recent studies in which signaling pathways regulating naturally-occurring axon regeneration that have been identified are reviewed, focusing on how these pathways control gene expression and growth-cone function during axon regeneration.

Keywords: axon regeneration, axonal growth, signal transduction

References

[1].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. doi: 10.1126/science.1161566. [DOI] [PMC free article] [PubMed] [Google Scholar]
[2].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. doi: 10.1038/nn.2603. [DOI] [PMC free article] [PubMed] [Google Scholar]
[3].Moore DL, Blackmore MG, Hu Y, Kaestner KH, Bixby JL, Lemmon VP, et al. KLF family members regulate intrinsic axon regeneration ability. Science. 2009;326:298–301. doi: 10.1126/science.1175737. [DOI] [PMC free article] [PubMed] [Google Scholar]
[4].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;480:372–375. doi: 10.1038/nature10594. [DOI] [PMC free article] [PubMed] [Google Scholar]
[5].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. doi: 10.1016/j.neuron.2009.11.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
[6].Wang Z, Jin Y. Genetic dissection of axon regeneration. Curr opin Neurobiol. 2011;21:189–196. doi: 10.1016/j.conb.2010.08.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
[7].Chen L, Chisholm AD. Axon regeneration mechanisms: insights from C. elegans. Trends Cell Biol. 2011;21:577–584. doi: 10.1016/j.tcb.2011.08.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
[8].El Bejjani R, Hammarlund M. Neural regeneration in Caenorhabditis elegans. Annu Rev Genet. 2012;46:499–513. doi: 10.1146/annurev-genet-110711-155550. [DOI] [PMC free article] [PubMed] [Google Scholar]
[9].Hammarlund M, Nix P, Hauth L, Jorgensen EM, Bastiani M. Axon regeneration requires a conserved MAP kinase pathway. Science. 2009;323:802–806. doi: 10.1126/science.1165527. [DOI] [PMC free article] [PubMed] [Google Scholar]
[10].Yanik MF, Cinar H, Cinar HN, Chisholm AD, Jin Y, Ben-Yakar A. Neurosurgery: functional regeneration after laser axotomy. Nature. 2004;432:822. doi: 10.1038/432822a. [DOI] [PubMed] [Google Scholar]
[11].Byrne AB, Edwards TJ, Hammarlund M. J Vis Exp. 2011. In vivo laser axotomy in C. elegans; p. e2707. [DOI] [PMC free article] [PubMed] [Google Scholar]
[12].Stone MC, Nguyen MM, Tao J, Allender DL, Rolls MM. Global up-regulation of microtubule dynamics and polarity reversal during regeneration of an axon from a dendrite. Mol Biol Cell. 2010;21:767–777. doi: 10.1091/mbc.E09-11-0967. [DOI] [PMC free article] [PubMed] [Google Scholar]
[13].O’Brien GS, Rieger S, Martin SM, Cavanaugh AM, Portera-Cailliau C, Sagasti A. J Vis Exp. 2009. Two-photon axotomy and time-lapse confocal imaging in live zebrafish embryos; p. 1129. [DOI] [PMC free article] [PubMed] [Google Scholar]
[14].Bradke F, Fawcett JW, Spira ME. Assembly of a new growth cone after axotomy: the precursor to axon regeneration. Nat Rev Neurosci. 2012;13:183–193. doi: 10.1038/nrn3176. [DOI] [PubMed] [Google Scholar]
[15].Hur EM, Saijilafu, Zhou FQ. Growing the growth cone: remodeling the cytoskeleton to promote axon regeneration. Trends Neurosci. 2012;35:164–174. doi: 10.1016/j.tins.2011.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
[16].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;138:1005–1018. doi: 10.1016/j.cell.2009.06.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
[17].Ghosh-Roy A, Goncharov A, Jin Y, Chisholm AD. Kinesin-13 and tubulin posttranslational modifications regulate microtubule growth in axon regeneration. Dev Cell. 2012;23:716–728. doi: 10.1016/j.devcel.2012.08.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
[18].Chen L, Wang Z, Ghosh-Roy A, Hubert T, Yan D, O’Rourke S, et al. Axon regeneration pathways identified by systematic genetic screening in C. elegans. Neuron. 2011;71:1043–1057. doi: 10.1016/j.neuron.2011.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
[19].Ghosh-Roy A, Wu Z, Goncharov A, Jin Y, Chisholm AD. Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase. J Neurosci. 2010;30:3175–3183. doi: 10.1523/JNEUROSCI.5464-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
[20].Pinan-Lucarre B, Gabel CV, Reina CP, Hulme SE, Shevkoplyas SS, Slone RD, et al. The core apoptotic executioner proteins CED-3 and CED-4 promote initiation of neuronal regeneration in Caenorhabditis elegans. PLoS Biol. 2012;10:e1001331. doi: 10.1371/journal.pbio.1001331. [DOI] [PMC free article] [PubMed] [Google Scholar]
[21].Nix P, Hisamoto N, Matsumoto K, Bastiani M. Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways. Proc Natl Acad Sci U S A. 2011;108:10738–10743. doi: 10.1073/pnas.1104830108. [DOI] [PMC free article] [PubMed] [Google Scholar]
[22].Leyssen M, Ayaz D, Hebert SS, Reeve S, De Strooper B, Hassan BA. Amyloid precursor protein promotes postdevelopmental neurite arborization in the Drosophila brain. EMBo J. 2005;24:2944–2955. doi: 10.1038/sj.emboj.7600757. [DOI] [PMC free article] [PubMed] [Google Scholar]
[23].Xiong X, Collins CA. A conditioning lesion protects axons from degeneration via the Wallenda/DLK MAP kinase signaling cascade. J Neurosci. 2012;32:610–615. doi: 10.1523/JNEUROSCI.3586-11.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
[24].Ayaz D, Leyssen M, Koch M, Yan J, Srahna M, Sheeba V, et al. Axonal injury and regeneration in the adult brain of Drosophila. J Neurosci. 2008;28:6010–6021. doi: 10.1523/JNEUROSCI.0101-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
[25].Barnat M, Enslen H, Propst F, Davis RJ, Soares S, Nothias F. Distinct roles of c-Jun N-terminal kinase isoforms in neurite initiation and elongation during axonal regeneration. J Neurosci. 2010;30:7804–7816. doi: 10.1523/JNEUROSCI.0372-10.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
[26].Chang L, Jones Y, Ellisman MH, Goldstein LS, Karin M. JNK1 is required for maintenance of neuronal microtubules and controls phosphorylation of microtubule-associated proteins. Dev Cell. 2003;4:521–533. doi: 10.1016/S1534-5807(03)00094-7. [DOI] [PubMed] [Google Scholar]
[27].Ciani L, Salinas PC. c-Jun N-terminal kinase (JNK) cooperates with Gsk3beta to regulate Dishevelled-mediated microtubule stability. BMC Cell Biol. 2007;8:27. doi: 10.1186/1471-2121-8-27. [DOI] [PMC free article] [PubMed] [Google Scholar]
[28].Tararuk T, Ostman N, Li W, Bjorkblom B, Padzik A, Zdrojewska J, et al. JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length. J Cell Biol. 2006;173:265–277. doi: 10.1083/jcb.200511055. [DOI] [PMC free article] [PubMed] [Google Scholar]
[29].Li C, Hisamoto N, Nix P, Kanao S, Mizuno T, Bastiani M, et al. The growth factor SVH-1 regulates axon regeneration in C. elegans via the JNK MAPK cascade. Nat Neurosci. 2012;15:551–557. doi: 10.1038/nn.3052. [DOI] [PubMed] [Google Scholar]
[30].Pastuhov S, Fujiki K, Nix P, Kanao S, Bastiani M, Matsumoto K, et al. Endocannabinoid-Goalpha signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqalpha-PKC-JNK signalling. Nat Commun. 2012;3:1136. doi: 10.1038/ncomms2136. [DOI] [PMC free article] [PubMed] [Google Scholar]
[31].El Bejjani R, Hammarlund M. Notch signaling inhibits axon regeneration. Neuron. 2012;73:268–278. doi: 10.1016/j.neuron.2011.11.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
[32].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;312:596–612. doi: 10.1016/j.ydbio.2007.09.019. [DOI] [PubMed] [Google Scholar]
[33].Veldman MB, Bemben MA, Goldman D. Tuba1a gene expression is regulated by KLF6/7 and is necessary for CNS development and regeneration in zebrafish. Mol Cell Neurosci. 2010;43:370–383. doi: 10.1016/j.mcn.2010.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
[34].Neumann S, Woolf CJ. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron. 1999;23:83–91. doi: 10.1016/S0896-6273(00)80755-2. [DOI] [PubMed] [Google Scholar]
[35].Neumann S, Skinner K, Basbaum AI. Sustaining intrinsic growth capacity of adult neurons promotes spinal cord regeneration. Proc Natl Acad Sci U S A. 2005;102:16848–16852. doi: 10.1073/pnas.0508538102. [DOI] [PMC free article] [PubMed] [Google Scholar]
[36].Ylera B, Erturk A, Hellal F, Nadrigny F, Hurtado A, Tahirovic S, et al. Chronically CNS-injured adult sensory neurons gain regenerative competence upon a lesion of their peripheral axon. Curr Biol. 2009;19:930–936. doi: 10.1016/j.cub.2009.04.017. [DOI] [PubMed] [Google Scholar]
[37].van Kesteren RE, Mason MR, Macgillavry HD, Smit AB, Verhaagen J. A gene network perspective on axonal regeneration. Front Mol Neurosci. 2011;4:46. doi: 10.3389/fnmol.2011.00046. [DOI] [PMC free article] [PubMed] [Google Scholar]
[38].Saijilafu, Hur EM, Zhou FQ. Genetic dissection of axon regeneration via in vivo electroporation of adult mouse sensory neurons. Nat Commun. 2011;2:543. doi: 10.1038/ncomms1568. [DOI] [PMC free article] [PubMed] [Google Scholar]
[39].Saijilafu, Zhou FQ. J Vis Exp. 2012. Genetic study of axon regeneration with cultured adult dorsal root ganglion neurons; p. e4141. [DOI] [PMC free article] [PubMed] [Google Scholar]
[40].Liu RY, Snider WD. Different signaling pathways mediate regenerative versus developmental sensory axon growth. J Neurosci. 2001;21:RC164. doi: 10.1523/JNEUROSCI.21-17-j0003.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
[41].Zhou FQ, Walzer M, Wu YH, Zhou J, Dedhar S, Snider WD. Neurotrophins support regenerative axon assembly over CSPGs by an ECM-integrin-independent mechanism. J Cell Sci. 2006;119:2787–2796. doi: 10.1242/jcs.03016. [DOI] [PubMed] [Google Scholar]
[42].Campenot RB. Development of sympathetic neurons in compartmentalized cultures. II. Local control of neurite survival by nerve growth factor. Dev Biol. 1982;93:13–21. doi: 10.1016/0012-1606(82)90233-0. [DOI] [PubMed] [Google Scholar]
[43].Campenot RB. Development of sympathetic neurons in compartmentalized cultures. II Local control of neurite growth by nerve growth factor. Dev Biol. 1982;93:1–12. doi: 10.1016/0012-1606(82)90232-9. [DOI] [PubMed] [Google Scholar]
[44].Taylor AM, Jeon NL. Microfluidic and compartmentalized platforms for neurobiological research. Crit Rev Biomed Eng. 2011;39:185–200. doi: 10.1615/CritRevBiomedEng.v39.i3.20. [DOI] [PubMed] [Google Scholar]
[45].Hur EM, Yang IH, Kim DH, Byun J, Saijilafu, Xu WL, et al. Engineering neuronal growth cones to promote axon regeneration over inhibitory molecules. Proc Natl Acad Sci U S A. 2011;108(12):5057–5062. doi: 10.1073/pnas.1011258108. [DOI] [PMC free article] [PubMed] [Google Scholar]
[46].Markus A, Zhong J, Snider WD. Raf and akt mediate distinct aspects of sensory axon growth. Neuron. 2002;35:65–76. doi: 10.1016/S0896-6273(02)00752-3. [DOI] [PubMed] [Google Scholar]
[47].Atwal JK, Massie B, Miller FD, Kaplan DR. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and Pi3-kinase. Neuron. 2000;27:265–277. doi: 10.1016/S0896-6273(00)00035-0. [DOI] [PubMed] [Google Scholar]
[48].Smith DS, Skene JH. A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth. J Neurosci. 1997;17:646–658. doi: 10.1523/JNEUROSCI.17-02-00646.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
[49].Diamond J, Coughlin M, Macintyre L, Holmes M, Visheau B. Evidence that endogenous beta nerve growth factor is responsible for the collateral sprouting, but not the regeneration, of nociceptive axons in adult rats. Proc Natl Acad Sci U S A. 1987;84:6596–6600. doi: 10.1073/pnas.84.18.6596. [DOI] [PMC free article] [PubMed] [Google Scholar]
[50].Lentz S, Miner JH, Sanes JR, Snider WD. Distribution of the ten known laminin chains in the pathways and targets of developing sensory axons. J Comp Neurol. 1997;378:547–561. doi: 10.1002/(SICI)1096-9861(19970224)378:4<547::AID-CNE9>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
[51].Werner A, Willem M, Jones LL, Kreutzberg GW, Mayer U, Raivich G. Impaired axonal regeneration in alpha7 integrindeficient mice. J Neurosci. 2000;20:1822–1830. doi: 10.1523/JNEUROSCI.20-05-01822.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
[52].Hur EM, Saijilafu, Lee BD, Kim SJ, Xu WL, Zhou FQ. GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules. Genes Dev. 2011;25:1968–1981. doi: 10.1101/gad.17015911. [DOI] [PMC free article] [PubMed] [Google Scholar]
[53].Jiang K, Akhmanova A. Microtubule tip-interacting proteins: a view from both ends. Curr opin Cell Biol. 2011;23:94–101. doi: 10.1016/j.ceb.2010.08.008. [DOI] [PubMed] [Google Scholar]
[54].Janke C, Bulinski JC. Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat Rev Mol Cell Biol. 2011;12:773–786. doi: 10.1038/nrm3227. [DOI] [PubMed] [Google Scholar]
[55].Cho Y, Cavalli V. HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration. EMBo J. 2012;31:3063–3078. doi: 10.1038/emboj.2012.160. [DOI] [PMC free article] [PubMed] [Google Scholar]
[56].Tedeschi A. Tuning the orchestra: transcriptional pathways controlling axon regeneration. Front Mol Neurosci. 2011;4:60. doi: 10.3389/fnmol.2011.00060. [DOI] [PMC free article] [PubMed] [Google Scholar]
[57].Liu CM, Hur EM, Zhou FQ. Coordinating gene expression and axon assembly to control axon growth: potential role of GSK3 signaling. Front Mol Neurosci. 2012;5:3. doi: 10.3389/fnmol.2012.00003. [DOI] [PMC free article] [PubMed] [Google Scholar]
[58].Eickholt BJ, Ahmed A, Davies M, Papakonstanti EA, Pearce W, Starkey ML, et al. Control of axonal growth and regeneration of sensory neurons by the p110delta Pi 3-kinase. PLoS one. 2007;2:e869. doi: 10.1371/journal.pone.0000869. [DOI] [PMC free article] [PubMed] [Google Scholar]
[59].Shin JE, Cho Y, Beirowski B, Milbrandt J, Cavalli V, DiAntonio A. Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron. 2012;74:1015–1022. doi: 10.1016/j.neuron.2012.04.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
[60].Itoh A, Horiuchi M, Bannerman P, Pleasure D, Itoh T. Impaired regenerative response of primary sensory neurons in ZPK/DLK gene-trap mice. Biochem Biophys Res Commun. 2009;383:258–262. doi: 10.1016/j.bbrc.2009.04.009. [DOI] [PubMed] [Google Scholar]
[61].Hirai S, de Cui F, Miyata T, Ogawa M, Kiyonari H, Suda Y, et al. The c-Jun N-terminal kinase activator dual leucine zipper kinase regulates axon growth and neuronal migration in the developing cerebral cortex. J Neurosci. 2006;26:11992–12002. doi: 10.1523/JNEUROSCI.2272-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
[62].Selvaraj BT, Frank N, Bender FL, Asan E, Sendtner M. Local axonal function of STAT3 rescues axon degeneration in the pmn model of motoneuron disease. J Cell Biol. 2012;199:437–451. doi: 10.1083/jcb.201203109. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR1] [1].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. doi: 10.1126/science.1161566. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR2] [2].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. doi: 10.1038/nn.2603. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR3] [3].Moore DL, Blackmore MG, Hu Y, Kaestner KH, Bixby JL, Lemmon VP, et al. KLF family members regulate intrinsic axon regeneration ability. Science. 2009;326:298–301. doi: 10.1126/science.1175737. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR4] [4].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;480:372–375. doi: 10.1038/nature10594. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR5] [5].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. doi: 10.1016/j.neuron.2009.11.021. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR6] [6].Wang Z, Jin Y. Genetic dissection of axon regeneration. Curr opin Neurobiol. 2011;21:189–196. doi: 10.1016/j.conb.2010.08.010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR7] [7].Chen L, Chisholm AD. Axon regeneration mechanisms: insights from C. elegans. Trends Cell Biol. 2011;21:577–584. doi: 10.1016/j.tcb.2011.08.003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR8] [8].El Bejjani R, Hammarlund M. Neural regeneration in Caenorhabditis elegans. Annu Rev Genet. 2012;46:499–513. doi: 10.1146/annurev-genet-110711-155550. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR9] [9].Hammarlund M, Nix P, Hauth L, Jorgensen EM, Bastiani M. Axon regeneration requires a conserved MAP kinase pathway. Science. 2009;323:802–806. doi: 10.1126/science.1165527. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR10] [10].Yanik MF, Cinar H, Cinar HN, Chisholm AD, Jin Y, Ben-Yakar A. Neurosurgery: functional regeneration after laser axotomy. Nature. 2004;432:822. doi: 10.1038/432822a. [DOI] [PubMed] [Google Scholar]

[CR11] [11].Byrne AB, Edwards TJ, Hammarlund M. J Vis Exp. 2011. In vivo laser axotomy in C. elegans; p. e2707. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR12] [12].Stone MC, Nguyen MM, Tao J, Allender DL, Rolls MM. Global up-regulation of microtubule dynamics and polarity reversal during regeneration of an axon from a dendrite. Mol Biol Cell. 2010;21:767–777. doi: 10.1091/mbc.E09-11-0967. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR13] [13].O’Brien GS, Rieger S, Martin SM, Cavanaugh AM, Portera-Cailliau C, Sagasti A. J Vis Exp. 2009. Two-photon axotomy and time-lapse confocal imaging in live zebrafish embryos; p. 1129. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR14] [14].Bradke F, Fawcett JW, Spira ME. Assembly of a new growth cone after axotomy: the precursor to axon regeneration. Nat Rev Neurosci. 2012;13:183–193. doi: 10.1038/nrn3176. [DOI] [PubMed] [Google Scholar]

[CR15] [15].Hur EM, Saijilafu, Zhou FQ. Growing the growth cone: remodeling the cytoskeleton to promote axon regeneration. Trends Neurosci. 2012;35:164–174. doi: 10.1016/j.tins.2011.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR16] [16].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;138:1005–1018. doi: 10.1016/j.cell.2009.06.023. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR17] [17].Ghosh-Roy A, Goncharov A, Jin Y, Chisholm AD. Kinesin-13 and tubulin posttranslational modifications regulate microtubule growth in axon regeneration. Dev Cell. 2012;23:716–728. doi: 10.1016/j.devcel.2012.08.010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR18] [18].Chen L, Wang Z, Ghosh-Roy A, Hubert T, Yan D, O’Rourke S, et al. Axon regeneration pathways identified by systematic genetic screening in C. elegans. Neuron. 2011;71:1043–1057. doi: 10.1016/j.neuron.2011.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR19] [19].Ghosh-Roy A, Wu Z, Goncharov A, Jin Y, Chisholm AD. Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase. J Neurosci. 2010;30:3175–3183. doi: 10.1523/JNEUROSCI.5464-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR20] [20].Pinan-Lucarre B, Gabel CV, Reina CP, Hulme SE, Shevkoplyas SS, Slone RD, et al. The core apoptotic executioner proteins CED-3 and CED-4 promote initiation of neuronal regeneration in Caenorhabditis elegans. PLoS Biol. 2012;10:e1001331. doi: 10.1371/journal.pbio.1001331. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR21] [21].Nix P, Hisamoto N, Matsumoto K, Bastiani M. Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways. Proc Natl Acad Sci U S A. 2011;108:10738–10743. doi: 10.1073/pnas.1104830108. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR22] [22].Leyssen M, Ayaz D, Hebert SS, Reeve S, De Strooper B, Hassan BA. Amyloid precursor protein promotes postdevelopmental neurite arborization in the Drosophila brain. EMBo J. 2005;24:2944–2955. doi: 10.1038/sj.emboj.7600757. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR23] [23].Xiong X, Collins CA. A conditioning lesion protects axons from degeneration via the Wallenda/DLK MAP kinase signaling cascade. J Neurosci. 2012;32:610–615. doi: 10.1523/JNEUROSCI.3586-11.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR24] [24].Ayaz D, Leyssen M, Koch M, Yan J, Srahna M, Sheeba V, et al. Axonal injury and regeneration in the adult brain of Drosophila. J Neurosci. 2008;28:6010–6021. doi: 10.1523/JNEUROSCI.0101-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR25] [25].Barnat M, Enslen H, Propst F, Davis RJ, Soares S, Nothias F. Distinct roles of c-Jun N-terminal kinase isoforms in neurite initiation and elongation during axonal regeneration. J Neurosci. 2010;30:7804–7816. doi: 10.1523/JNEUROSCI.0372-10.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR26] [26].Chang L, Jones Y, Ellisman MH, Goldstein LS, Karin M. JNK1 is required for maintenance of neuronal microtubules and controls phosphorylation of microtubule-associated proteins. Dev Cell. 2003;4:521–533. doi: 10.1016/S1534-5807(03)00094-7. [DOI] [PubMed] [Google Scholar]

[CR27] [27].Ciani L, Salinas PC. c-Jun N-terminal kinase (JNK) cooperates with Gsk3beta to regulate Dishevelled-mediated microtubule stability. BMC Cell Biol. 2007;8:27. doi: 10.1186/1471-2121-8-27. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR28] [28].Tararuk T, Ostman N, Li W, Bjorkblom B, Padzik A, Zdrojewska J, et al. JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length. J Cell Biol. 2006;173:265–277. doi: 10.1083/jcb.200511055. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR29] [29].Li C, Hisamoto N, Nix P, Kanao S, Mizuno T, Bastiani M, et al. The growth factor SVH-1 regulates axon regeneration in C. elegans via the JNK MAPK cascade. Nat Neurosci. 2012;15:551–557. doi: 10.1038/nn.3052. [DOI] [PubMed] [Google Scholar]

[CR30] [30].Pastuhov S, Fujiki K, Nix P, Kanao S, Bastiani M, Matsumoto K, et al. Endocannabinoid-Goalpha signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqalpha-PKC-JNK signalling. Nat Commun. 2012;3:1136. doi: 10.1038/ncomms2136. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR31] [31].El Bejjani R, Hammarlund M. Notch signaling inhibits axon regeneration. Neuron. 2012;73:268–278. doi: 10.1016/j.neuron.2011.11.017. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR32] [32].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;312:596–612. doi: 10.1016/j.ydbio.2007.09.019. [DOI] [PubMed] [Google Scholar]

[CR33] [33].Veldman MB, Bemben MA, Goldman D. Tuba1a gene expression is regulated by KLF6/7 and is necessary for CNS development and regeneration in zebrafish. Mol Cell Neurosci. 2010;43:370–383. doi: 10.1016/j.mcn.2010.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR34] [34].Neumann S, Woolf CJ. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron. 1999;23:83–91. doi: 10.1016/S0896-6273(00)80755-2. [DOI] [PubMed] [Google Scholar]

[CR35] [35].Neumann S, Skinner K, Basbaum AI. Sustaining intrinsic growth capacity of adult neurons promotes spinal cord regeneration. Proc Natl Acad Sci U S A. 2005;102:16848–16852. doi: 10.1073/pnas.0508538102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR36] [36].Ylera B, Erturk A, Hellal F, Nadrigny F, Hurtado A, Tahirovic S, et al. Chronically CNS-injured adult sensory neurons gain regenerative competence upon a lesion of their peripheral axon. Curr Biol. 2009;19:930–936. doi: 10.1016/j.cub.2009.04.017. [DOI] [PubMed] [Google Scholar]

[CR37] [37].van Kesteren RE, Mason MR, Macgillavry HD, Smit AB, Verhaagen J. A gene network perspective on axonal regeneration. Front Mol Neurosci. 2011;4:46. doi: 10.3389/fnmol.2011.00046. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR38] [38].Saijilafu, Hur EM, Zhou FQ. Genetic dissection of axon regeneration via in vivo electroporation of adult mouse sensory neurons. Nat Commun. 2011;2:543. doi: 10.1038/ncomms1568. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR39] [39].Saijilafu, Zhou FQ. J Vis Exp. 2012. Genetic study of axon regeneration with cultured adult dorsal root ganglion neurons; p. e4141. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR40] [40].Liu RY, Snider WD. Different signaling pathways mediate regenerative versus developmental sensory axon growth. J Neurosci. 2001;21:RC164. doi: 10.1523/JNEUROSCI.21-17-j0003.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR41] [41].Zhou FQ, Walzer M, Wu YH, Zhou J, Dedhar S, Snider WD. Neurotrophins support regenerative axon assembly over CSPGs by an ECM-integrin-independent mechanism. J Cell Sci. 2006;119:2787–2796. doi: 10.1242/jcs.03016. [DOI] [PubMed] [Google Scholar]

[CR42] [42].Campenot RB. Development of sympathetic neurons in compartmentalized cultures. II. Local control of neurite survival by nerve growth factor. Dev Biol. 1982;93:13–21. doi: 10.1016/0012-1606(82)90233-0. [DOI] [PubMed] [Google Scholar]

[CR43] [43].Campenot RB. Development of sympathetic neurons in compartmentalized cultures. II Local control of neurite growth by nerve growth factor. Dev Biol. 1982;93:1–12. doi: 10.1016/0012-1606(82)90232-9. [DOI] [PubMed] [Google Scholar]

[CR44] [44].Taylor AM, Jeon NL. Microfluidic and compartmentalized platforms for neurobiological research. Crit Rev Biomed Eng. 2011;39:185–200. doi: 10.1615/CritRevBiomedEng.v39.i3.20. [DOI] [PubMed] [Google Scholar]

[CR45] [45].Hur EM, Yang IH, Kim DH, Byun J, Saijilafu, Xu WL, et al. Engineering neuronal growth cones to promote axon regeneration over inhibitory molecules. Proc Natl Acad Sci U S A. 2011;108(12):5057–5062. doi: 10.1073/pnas.1011258108. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR46] [46].Markus A, Zhong J, Snider WD. Raf and akt mediate distinct aspects of sensory axon growth. Neuron. 2002;35:65–76. doi: 10.1016/S0896-6273(02)00752-3. [DOI] [PubMed] [Google Scholar]

[CR47] [47].Atwal JK, Massie B, Miller FD, Kaplan DR. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and Pi3-kinase. Neuron. 2000;27:265–277. doi: 10.1016/S0896-6273(00)00035-0. [DOI] [PubMed] [Google Scholar]

[CR48] [48].Smith DS, Skene JH. A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth. J Neurosci. 1997;17:646–658. doi: 10.1523/JNEUROSCI.17-02-00646.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR49] [49].Diamond J, Coughlin M, Macintyre L, Holmes M, Visheau B. Evidence that endogenous beta nerve growth factor is responsible for the collateral sprouting, but not the regeneration, of nociceptive axons in adult rats. Proc Natl Acad Sci U S A. 1987;84:6596–6600. doi: 10.1073/pnas.84.18.6596. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR50] [50].Lentz S, Miner JH, Sanes JR, Snider WD. Distribution of the ten known laminin chains in the pathways and targets of developing sensory axons. J Comp Neurol. 1997;378:547–561. doi: 10.1002/(SICI)1096-9861(19970224)378:4<547::AID-CNE9>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]

[CR51] [51].Werner A, Willem M, Jones LL, Kreutzberg GW, Mayer U, Raivich G. Impaired axonal regeneration in alpha7 integrindeficient mice. J Neurosci. 2000;20:1822–1830. doi: 10.1523/JNEUROSCI.20-05-01822.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR52] [52].Hur EM, Saijilafu, Lee BD, Kim SJ, Xu WL, Zhou FQ. GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules. Genes Dev. 2011;25:1968–1981. doi: 10.1101/gad.17015911. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR53] [53].Jiang K, Akhmanova A. Microtubule tip-interacting proteins: a view from both ends. Curr opin Cell Biol. 2011;23:94–101. doi: 10.1016/j.ceb.2010.08.008. [DOI] [PubMed] [Google Scholar]

[CR54] [54].Janke C, Bulinski JC. Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat Rev Mol Cell Biol. 2011;12:773–786. doi: 10.1038/nrm3227. [DOI] [PubMed] [Google Scholar]

[CR55] [55].Cho Y, Cavalli V. HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration. EMBo J. 2012;31:3063–3078. doi: 10.1038/emboj.2012.160. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR56] [56].Tedeschi A. Tuning the orchestra: transcriptional pathways controlling axon regeneration. Front Mol Neurosci. 2011;4:60. doi: 10.3389/fnmol.2011.00060. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR57] [57].Liu CM, Hur EM, Zhou FQ. Coordinating gene expression and axon assembly to control axon growth: potential role of GSK3 signaling. Front Mol Neurosci. 2012;5:3. doi: 10.3389/fnmol.2012.00003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR58] [58].Eickholt BJ, Ahmed A, Davies M, Papakonstanti EA, Pearce W, Starkey ML, et al. Control of axonal growth and regeneration of sensory neurons by the p110delta Pi 3-kinase. PLoS one. 2007;2:e869. doi: 10.1371/journal.pone.0000869. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR59] [59].Shin JE, Cho Y, Beirowski B, Milbrandt J, Cavalli V, DiAntonio A. Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron. 2012;74:1015–1022. doi: 10.1016/j.neuron.2012.04.028. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR60] [60].Itoh A, Horiuchi M, Bannerman P, Pleasure D, Itoh T. Impaired regenerative response of primary sensory neurons in ZPK/DLK gene-trap mice. Biochem Biophys Res Commun. 2009;383:258–262. doi: 10.1016/j.bbrc.2009.04.009. [DOI] [PubMed] [Google Scholar]

[CR61] [61].Hirai S, de Cui F, Miyata T, Ogawa M, Kiyonari H, Suda Y, et al. The c-Jun N-terminal kinase activator dual leucine zipper kinase regulates axon growth and neuronal migration in the developing cerebral cortex. J Neurosci. 2006;26:11992–12002. doi: 10.1523/JNEUROSCI.2272-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR62] [62].Selvaraj BT, Frank N, Bender FL, Asan E, Sendtner M. Local axonal function of STAT3 rescues axon degeneration in the pmn model of motoneuron disease. J Cell Biol. 2012;199:437–451. doi: 10.1083/jcb.201203109. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Signaling pathways that regulate axon regeneration

Saijilafu

Bo-Yin Zhang

Feng-Quan Zhou

Abstract

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Signaling pathways that regulate axon regeneration

Saijilafu

Bo-Yin Zhang

Feng-Quan Zhou

Abstract

References

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases