Please wait a minute...
浙江大学学报（医学版）
J Zhejiang Univ (Med Sci)  2020, Vol. 49 Issue (4): 500-507    DOI: 10.3785/j.issn.1008-9292.2020.08.15
    
Progress on axon regeneration in model organisms
JIANG Peiran(),WANG Zhiping*()
School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China
Download: HTML( 4 )   PDF(2155KB)
Export: BibTeX | EndNote (RIS)      

Abstract  

Different from neurons in the peripheral nervous system, mature neurons in the mammalian central nervous system often fail to regenerate after injury. Recent studies have found that calcium transduction, injury signaling, mitochondrial transportation, cytoskeletal remodeling and protein synthesis play essential roles in axon regeneration. Firstly, axon injury increases the intracellular concentration of calcium, and initiates the injury signaling pathways including cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and dual leucine kinase (DLK), which are found to promote axon regeneration in multiple animal injury models. The second step for axonal regrowth is to rebuild growth cones. Overexpressing proteins that promote dynamics of microtubules and actin filaments is beneficial for the reassembly of cytoskeletons and initiation of new growth cones. Thirdly, mitochondria, the power factory for cells, also play important roles in growth cone formation and axonal extension. The last but not the least important step is the regulation of gene transcription and protein translation to sustain the regrowth of axons. This review summarizes important findings revealing the functions and mechanisms of these biological progresses.

Key words： Axon      Regeneration      Mitochondrial transportation      Model organisms      Review     
Received: 20 May 2020      Published: 27 September 2020
CLC:  R338  
Corresponding Authors: WANG Zhiping     E-mail: peiranjiang@zju.edu.cn;z4wang@zju.edu.cn
Service
E-mail this article
Add to my bookshelf
Add to citation manager
E-mail Alert
RSS
Articles by authors
JIANG Peiran
WANG Zhiping
Cite this article:

JIANG Peiran,WANG Zhiping. Progress on axon regeneration in model organisms. J Zhejiang Univ (Med Sci), 2020, 49(4): 500-507.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.08.15     OR     http://www.zjujournals.com/med/Y2020/V49/I4/500


模式生物神经轴突再生的研究进展

与外周神经系统的神经元不同，中枢神经系统中成熟的神经元往往无法实现损伤后再生。近期，有研究发现钙离子传导损伤信号、线粒体运输、细胞骨架重构和蛋白质合成在轴突再生中发挥重要的功能。神经元损伤发生后，细胞内钙离子浓度升高，通过钙离子介导的环腺苷酸（cAMP）-蛋白激酶A（PKA）信号通路活化可激活下游双亮氨酸激酶（DLK），在多种动物损伤模型中促进轴突再生。轴突再生需要生长锥的重构，这一进程需要细胞骨架的有序组装，在损伤处表达特定促进微管和微丝聚合的基因可有效促进生长锥的重构。此外，负责供能的线粒体也会影响生长锥的重构和轴突再生能力。最后，研究还发现多个调控基因表达与蛋白合成的通路可促进轴突再生。本综述将重点概括这些对轴突再生有重要作用的生理过程和分子机制。


关键词： 轴突,  再生,  线粒体运输,  模式生物,  综述 
Fig 1 Schematic diagram of post-injury axon regeneration
与生理进程相关的基因和分子 对轴突再生的影响 作用机制 参考文献序号
MAPKKK：促分裂原活化的蛋白激酶激酶激酶；MAPKK：促分裂原活化的蛋白激酶激酶；MAPK：丝裂原激活蛋白激酶；CSPG：硫酸软骨素蛋白多糖；Nogo：勿动蛋白；GAP-43：生长相关蛋白43；CAP-23：皮质细胞骨架相关蛋白23；HDAC5：组蛋白去乙酰基酶5；cofilin1：肌动蛋白解聚因子；Tat-beclin1：一种诱导自噬的重组多肽；Fidgetin：一种微管切割蛋白；ARMCX1：哺乳动物特有的一种线粒体蛋白；Miro1：线粒体的Rho GTP酶1；mTOR：哺乳动物雷帕霉素靶蛋白；c-myc：核内癌基因；p53：人体抑癌基因；SOCS3：细胞因子信号抑制物3；PTEN：磷酸酶和张力蛋白同源物.
损伤信号感知
    环腺苷酸 促进 背根神经节分支发生损伤时，内源性环腺苷酸大量生成，通过蛋白激酶A激活轴突损伤后再生 6
  双亮氨酸激酶1 促进 MAPKKK家族成员，通过调控MAPKK的活性，稳定MAPK激活相关基因增强子结合蛋白1 mRNA，从而调控突触形成和轴突形态 7
  CSPG 抑制 细胞外抑制性因子，由损伤部位的星形胶质细胞分泌，抑制轴突再生 23
  Nogo 抑制 细胞外抑制性因子，由损伤部位的髓鞘碎片分泌，抑制轴突再生 24
细胞骨架重构
  GAP-43 & CAP-23 促进 生长锥蛋白，促进体外背根神经节的延伸 31
  HDAC5 促进 过表达HDAC5后，促进背根神经节损伤后轴突再生 30
  cofilin1 促进 仅过表达该基因即可实现显著的脊髓损伤后轴突再生 33
  Tat-beclin1 促进 通过降解微管解聚蛋白SCG10来提高微管的稳定性从而促进轴突再生 27
  Fidgetin 抑制 背根神经节中条件性敲降该蛋白表达，可实现损伤后神经突起损伤区域与脊髓的再连接 28
线粒体运输
  ARMCX1 促进 ARMCX1通过与Miro1互作，影响后者与Trak1/2驱动蛋白复合体的连接，调节视网膜神经节细胞线粒体的运输 32
  重组人生长蛋白 抑制 编码Syntaphilin，敲除重组人生长蛋白可使背根神经节轴突重获生长能力 37
基因表达与蛋白合成
  mTOR 促进 通过下游S6K1促进蛋白生成和轴突再生 39
  c-Myc 促进 核内癌基因，是禽类骨髓细胞瘤病毒转化序列的细胞同源物，可促进视网膜神经节细胞损伤模型的轴突再生 46
  p53 促进 抑癌基因，在细胞增殖、分化等过程中起重要转录调控作用，可促进感觉神经元的轴突再生 36
  SOCS3 抑制 轴突损伤时由炎症因子介导该基因表达上调，维持炎性反应，敲除该基因可促进轴突再生 44
  PTEN 抑制 磷酸酶和肌腱蛋白同源物，负向调控mTOR信号通路，在视网膜神经节细胞损伤后抑制轴突再生 45
Tab 1 Key genes and molecules involved in regulation of axon regeneration
[1]   SHINN E, PATE A, PINTO F, et al. Long-term outcomes after mild traumatic brain injury[J/OL]. J Am Coll Surgeons, 2014, 219(4, Supplement): e144-e145. DOI: 10.1016/j.jamcollsurg.2014.07.775.
[2]   HE Z , JIN Y . Intrinsic control of axon regeneration[J]. Neuron, 2016, 90 (3): 437- 451
doi: 10.1016/j.neuron.2016.04.022
[3]   HAMMARLUND M , JIN Y . Axon regeneration in C. elegans[J]. Curr Opin Neurobiol, 2014, 27 199- 207
doi: 10.1016/j.conb.2014.04.001
[4]   CHEN L , WANG Z , GHOSH-ROY A et al. Axon regeneration pathways identified by systematic genetic screening in C. elegans[J]. Neuron, 2011, 71 (6): 1043- 1057
doi: 10.1016/j.neuron.2011.07.009
[5]   EDWARDS T J , HAMMARLUND M . Syndecan promotes axon regeneration by stabilizing growth cone migration[J]. Cell Rep, 2014, 8 (1): 272- 283
doi: 10.1016/j.celrep.2014.06.008
[6]   QIU J , CAI D , DAI H et al. Spinal axon regeneration induced by elevation of cyclic AMP[J]. Neuron, 2002, 34 (6): 895- 903
doi: 10.1016/S0896-6273(02)00730-4
[7]   YAN D , WU Z , CHISHOLM A D et al. The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration[J]. Cell, 2009, 138 (5): 1005- 1018
doi: 10.1016/j.cell.2009.06.023
[8]   QIU J , CAI D , DAI H et al. Spinal axon regeneration induced by elevation of cyclic AMP[J]. Neuron, 2002, 34 (6): 895- 903
doi: 10.1016/S0896-6273(02)00730-4
[9]   GHOSH-ROY A , WU Z , GONCHAROV A et al. Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase[J]. J Neurosci, 2010, 30 (9): 3175- 3183
doi: 10.1523/JNEUROSCI.5464-09.2010
[10]   YAN D , WU Z , CHISHOLM A D et al. The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration[J]. Cell, 2009, 138 (5): 1005- 1018
doi: 10.1016/j.cell.2009.06.023
[11]   GHOSH-ROY A , WU Z , GONCHAROV A et al. Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase[J]. J Neurosci, 2010, 30 (9): 3175- 3183
doi: 10.1523/JNEUROSCI.5464-09.2010
[12]   PEARSE D D , PEREIRA F C , MARCILLO A E et al. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury[J]. Nat Med, 2004, 10 (6): 610- 616
doi: 10.1038/nm1056
[13]   HAO Y , FREY E , YOON C et al. An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the dual leucine zipper kinase DLK[J]. Elife, 2016, 5
doi: 10.7554/eLife.14048
[14]   NIKOLAEVA M A , MUKHERJEE B , STYS P K . Na+-dependent sources of intra-axonal Ca2+ release in rat optic nerve during in vitro chemical ischemia[J]. J Neurosci, 2005, 25 (43): 9960- 9967
doi: 10.1523/JNEUROSCI.2003-05.2005
[15]   GIROUARD M P , BUENO M , JULIAN V et al. The molecular interplay between axon degeneration and regeneration[J]. Dev Neurobiol, 2018, 78 (10): 978- 990
doi: 10.1002/dneu.22627
[16]   BROWN M C , LUNN E R , PERRY V H . Consequences of slow Wallerian degeneration for regenerating motor and sensory axons[J]. J Neurobiol, 1992, 23 (5): 521- 536
doi: 10.1002/neu.480230507
[17]   WATKINS T A , WANG B , HUNTWORK-RODRIGUEZ S et al. DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury[J]. Proc Natl Acad Sci U S A, 2013, 110 (10): 4039- 4044
doi: 10.1073/pnas.1211074110
[18]   NIMMERJAHN A , KIRCHHOFF F , HELMCHEN F . Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo[J]. Science, 2005, 308 (5726): 1314- 1318
doi: 10.1126/science.1110647
[19]   NEUMANN H , KOTTER M R , FRANKLIN R J . Debris clearance by microglia:an essential link between degeneration and regeneration[J]. Brain, 2009, 132 (Pt 2): 288- 295
doi: 10.1093/brain/awn109
[20]   HILLA A M , DIEKMANN H , FISCHER D . Microglia are irrelevant for neuronal degeneration and axon regeneration after acute injury[J]. J Neurosci, 2017, 37 (25): 6113- 6124
doi: 10.1523/JNEUROSCI.0584-17.2017
[21]   CONDE C , CáCERES A . Microtubule assembly, organization and dynamics in axons and dendrites[J]. Nat Rev Neurosci, 2009, 10 (5): 319- 332
doi: 10.1038/nrn2631
[22]   SCHIFF P B , HORWITZ S B . Taxol stabilizes microtubules in mouse fibroblast cells[J]. Proc Natl Acad Sci U S A, 1980, 77 (3): 1561- 1565
doi: 10.1073/pnas.77.3.1561
[23]   YIU G , HE Z . Glial inhibition of CNS axon regeneration[J]. Nat Rev Neurosci, 2006, 7 (8): 617- 627
doi: 10.1038/nrn1956
[24]   SCHWAB M E . Nogo and axon regeneration[J]. Curr Opin Neurobiol, 2004, 14 (1): 118- 124
doi: 10.1016/j.conb.2004.01.004
[25]   SENGOTTUVEL V , LEIBINGER M , PFREIMER M et al. Taxol facilitates axon regeneration in the mature CNS[J]. J Neurosci, 2011, 31 (7): 2688- 2699
doi: 10.1523/JNEUROSCI.4885-10.2011
[26]   RUSCHEL J , HELLAL F , FLYNN K C et al. Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury[J]. Science, 2015, 348 (6232): 347- 352
doi: 10.1126/science.aaa2958
[27]   HE M , DING Y , CHU C et al. Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury[J]. Proc Natl Acad Sci U S A, 2016, 113 (40): 11324- 11329
doi: 10.1073/pnas.1611282113
[28]   MATAMOROS A J , TOM V J , WU D et al. Knockdown of fidgetin improves regeneration of injured axons by a microtubule-based mechanism[J]. J Neurosci, 2019, 39 (11): 2011- 2024
doi: 10.1523/JNEUROSCI.1888-18.2018
[29]   PERIS L , WAGENBACH M , LAFANECHèRE L et al. Motor-dependent microtubule disassembly driven by tubulin tyrosination[J]. J Cell Biol, 2009, 185 (7): 1159- 1166
doi: 10.1083/jcb.200902142
[30]   CHO Y , CAVALLI V . HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration[J]. EMBO J, 2012, 31 (14): 3063- 3078
doi: 10.1038/emboj.2012.160
[31]   BOMZE H M , BULSARA K R , ISKANDAR B J et al. Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons[J]. Nat Neurosci, 2001, 4 (1): 38- 43
doi: 10.1038/82881
[32]   CARTONI R , NORSWORTHY M W , BEI F et al. The mammalian-specific protein armcx1 regulates mitochondrial transport during axon regeneration[J]. Neuron, 2016, 92 (6): 1294- 1307
doi: 10.1016/j.neuron.2016.10.060
[33]   TEDESCHI A , DUPRAZ S , CURCIO M et al. ADF/Cofilin-mediated actin turnover promotes axon regeneration in the adult CNS[J]. Neuron, 2019, 103 (6): 1073- 1085
doi: 10.1016/j.neuron.2019.07.007
[34]   LI Z , OKAMOTO K , HAYASHI Y et al. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses[J]. Cell, 2004, 119 (6): 873- 887
doi: 10.1016/j.cell.2004.11.003
[35]   MORRIS R L , HOLLENBECK P J . The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth[J]. J Cell Sci, 1993, 104 (Pt 3): 917- 927
[36]   BELIN S , NAWABI H , WANG C et al. Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics[J]. Neuron, 2015, 86 (4): 1000- 1014
doi: 10.1016/j.neuron.2015.03.060
[37]   ZHOU B , YU P , LIN M Y et al. Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits[J]. J Cell Biol, 2016, 214 (1): 103- 119
doi: 10.1083/jcb.201605101
[38]   WU D , LEE S , LUO J et al. Intraneural injection of ATP stimulates regeneration of primary sensory axons in the spinal cord[J]. J Neurosci, 2018, 38 (6): 1351- 1365
doi: 10.1523/JNEUROSCI.1660-17.2017
[39]   PARK K K , LIU K , HU Y et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway[J]. Science, 2008, 322 (5903): 963- 966
doi: 10.1126/science.1161566
[40]   DU K , ZHENG S , ZHANG Q et al. Pten deletion promotes regrowth of corticospinal tract axons 1 year after spinal cord injury[J]. J Neurosci, 2015, 35 (26): 9754- 9763
doi: 10.1523/JNEUROSCI.3637-14.2015
[41]   SUN F , PARK K K , BELIN S et al. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3[J]. Nature, 2011, 480 (7377): 372- 375
doi: 10.1038/nature10594
[42]   YANG L , MIAO L , LIANG F et al. The mTORC1 effectors S6K1 and 4E-BP play different roles in CNS axon regeneration[J]. Nat Commun, 2014, 5 5416
doi: 10.1038/ncomms6416
[43]   JIN D , LIU Y , SUN F et al. Restoration of skilled locomotion by sprouting corticospinal axons induced by co-deletion of PTEN and SOCS3[J]. Nat Commun, 2015, 6 8074
doi: 10.1038/ncomms9074
[44]   SMITH P D , SUN F , PARK K K et al. SOCS3 deletion promotes optic nerve regeneration in vivo[J]. Neuron, 2009, 64 (5): 617- 623
doi: 10.1016/j.neuron.2009.11.021
[45]   MA J J , JU X , XU R J et al. Telomerase reverse transcriptase and p53 regulate mammalian peripheral nervous system and CNS axon regeneration downstream of c-Myc[J]. J Neurosci, 2019, 39 (46): 9107- 9118
doi: 10.1523/JNEUROSCI.0419-19.2019
[46]   ZHANG Y , WILLIAMS P R , JACOBI A et al. Elevating growth factor responsiveness and axon regeneration by modulating presynaptic inputs[J]. Neuron, 2019, 103 (1): 39- 51
doi: 10.1016/j.neuron.2019.04.033
[1] XU Qinglin,LOU Guodong,WANG Tiantian,ZHANG Lisan. Advances in treatment of narcolepsy[J]. J Zhejiang Univ (Med Sci), 2020, 49(4): 419-424.
[2] YU Qing, XIONG Xiufang, SUN Yi. Targeting Cullin-RING E3 ligases for anti-cancer therapy: efforts on drug discovery[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 1-19.
[3] DUAN Lingyan,YIN Xiangju,MENG Hong'en,FANG Xuexian,MIN Junxia,WANG Fudi. Progress on epigenetic regulation of iron homeostasis[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 58-70.
[4] LI Ai,ZHANG Tianyuan,GAO Jianqing. Progress on utilizing mesenchymal stem cells as cellular delivery system for targeting delivery of as drug/gene for anti-tumor therapy[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 20-34.
[5] HUANG Yaoping,YANG Feng,ZHOU Tianhua,XIE Shanshan. Emerging roles of Hippo signaling pathway in gastrointestinal cancers and its molecular mechanisms[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 35-43.
[6] ZHONG Wen,LOU Yan,QIU Chenyang,LI Donglin,ZHANG Hongkun. Antithrombotic therapy after iliac vein stenting[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 131-136.
[7] XU Yiming,YING Kejing. Research progress on neutrophil extracellular traps in tumor[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 107-112.
[8] LIU Xiaoxiao,GUO Liqiong,LIANG Cheng. Research progress on electroencephalogram characteristics of anti-N-methyl-D-aspartate receptor encephalitis[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 118-123.
[9] FANG Juan,PAN Zhicheng,GUO Xiaogang. Research advance of ANRIL on atherosclerosis by regulating cell proliferation and apoptosis[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 113-117.
[10] WANG Shiying,GU Xinhua. Progress on clinical application of orthodontic-implant combined therapy[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 124-130.
[11] WANG Yifeng, WANG Zhiping. Research progress on intrinsic signaling pathways in axon regeneration[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 82-89.
[12] ZHAO Weixia,ZOU Wei. Intrinsic and extrinsic mechanisms regulating neuronal dendrite morphogenesis[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 90-99.
[13] WANG Yi,LU Yunbi. Poly adenosine diphosphate-ribosylation and neurodegenerative diseases[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 100-106.
[14] CHEN Junyi,YANG Xiang,FANG Xuexian,WANG Fudi,MIN Junxia. The role of ferroptosis in chronic diseases[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 44-57.
[15] DING Yidan,LI Wenbin,WANG Rong,ZHANG Jianchun. Research progress on the effects of plateau hypoxia on blood-brain barrier structure and drug permeability[J]. J Zhejiang Univ (Med Sci), 2019, 48(6): 668-673.