Home LiteratureArticle Details
PMID: 22334213 Published · epublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review

Assembly of a new growth cone after axotomy: the precursor to axon regeneration.

Nature reviews. Neuroscience ·Vol. 13 ·No. 3 ·2012-02-15 ·Pages 183-93

Bradke F, Fawcett JW, Spira ME

Abstract

The assembly of a new growth cone is a prerequisite for axon regeneration after injury. Creation of a new growth cone involves multiple processes, including calcium signalling, restructuring of the cytoskeleton, transport of materials, local translation of messenger RNAs and the insertion of new membrane and cell surface molecules. In axons that have an intrinsic ability to regenerate, these processes are executed in a timely fashion. However, in axons that lack regenerative capacity, such as those of the mammalian CNS, several of the steps that are required for regeneration fail, and these axons do not begin the growth process. Identification of the points of failure can suggest targets for promoting regeneration.

MeSH Terms
Animals Axons/physiology Axotomy Calcium Signaling/physiology Cytoskeleton/physiology Growth Cones/physiology Nerve Regeneration/physiology
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Bradke Frank
Axonal Growth and Regeneration, German Center for Neurodegenerative Disease, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
Fawcett James W
Spira Micha E
References (101)
101 references, click to expand
  1. Neuronal polarity: vectorial cytoplasmic flow precedes axon formation.
    Neuron. 1997 Dec;19(6):1175-86 PMID: 9427242
  2. Localized and transient elevations of intracellular Ca2+ induce the dedifferentiation of axonal segments into growth cones.
    J Neurosci. 1997 May 15;17(10):3568-79 PMID: 9133380
  3. Continuous membrane-cytoskeleton adhesion requires continuous accommodation to lipid and cytoskeleton dynamics.
    Annu Rev Biophys Biomol Struct. 2006;35:417-34 PMID: 16689643
  4. Acute physiological response of mammalian central neurons to axotomy: ionic regulation and electrical activity.
    FASEB J. 2004 Dec;18(15):1934-6 PMID: 15451889
  5. Asymmetrical beta-actin mRNA translation in growth cones mediates attractive turning to netrin-1.
    Nat Neurosci. 2006 Oct;9(10):1247-56 PMID: 16980963
  6. Chronically CNS-injured adult sensory neurons gain regenerative competence upon a lesion of their peripheral axon.
    Curr Biol. 2009 Jun 9;19(11):930-6 PMID: 19409789
  7. Dynamics of axonal mRNA transport and implications for peripheral nerve regeneration.
    Exp Neurol. 2010 May;223(1):19-27 PMID: 19699200
  8. Binding of calpain fragments to calpastatin.
    J Biol Chem. 1991 Jun 25;266(18):11842-50 PMID: 2050681
  9. The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration.
    Cell. 2009 Sep 4;138(5):1005-18 PMID: 19737525
  10. Critical calpain-dependent ultrastructural alterations underlie the transformation of an axonal segment into a growth cone after axotomy of cultured Aplysia neurons.
    J Comp Neurol. 2003 Mar 10;457(3):293-312 PMID: 12541311
  11. Electrical activity suppresses axon growth through Ca(v)1.2 channels in adult primary sensory neurons.
    Curr Biol. 2010 Jul 13;20(13):1154-64 PMID: 20579880
  12. Phosphatidylcholine biosynthesis via CTP:phosphocholine cytidylyltransferase 2 facilitates neurite outgrowth and branching.
    J Biol Chem. 2008 Jan 4;283(1):202-212 PMID: 17981805
  13. Axonal mRNAs: characterisation and role in the growth and regeneration of dorsal root ganglion axons and growth cones.
    Mol Cell Neurosci. 2009 Oct;42(2):102-115 PMID: 19520167
  14. The axon initial segment and the maintenance of neuronal polarity.
    Nat Rev Neurosci. 2010 Aug;11(8):552-62 PMID: 20631711
  15. Short window of opportunity for calpain induced growth cone formation after axotomy of Aplysia neurons.
    J Neurobiol. 2002 Sep 15;52(4):267-79 PMID: 12210094
  16. Formation of microtubule-based traps controls the sorting and concentration of vesicles to restricted sites of regenerating neurons after axotomy.
    J Cell Biol. 2007 Feb 12;176(4):497-507 PMID: 17283182
  17. Functions of Nogo proteins and their receptors in the nervous system.
    Nat Rev Neurosci. 2010 Dec;11(12):799-811 PMID: 21045861
  18. Retrograde signaling in axonal regeneration.
    Exp Neurol. 2010 May;223(1):5-10 PMID: 19699198
  19. PTEN/mTOR and axon regeneration.
    Exp Neurol. 2010 May;223(1):45-50 PMID: 20079353
  20. Conditioning injury-induced spinal axon regeneration fails in interleukin-6 knock-out mice.
    J Neurosci. 2004 May 5;24(18):4432-43 PMID: 15128857
  21. Imaging and analysis of evoked excitatory-postsynaptic-calcium-transients by individual presynaptic-boutons of cultured Aplysia sensorimotor synapse.
    Cell Calcium. 2010 Apr;47(4):315-25 PMID: 20089302
  22. Schwann cell to axon transfer of ribosomes: toward a novel understanding of the role of glia in the nervous system.
    J Neurosci. 2008 Oct 22;28(43):11024-9 PMID: 18945910
  23. Effects of neurotoxic and neuroprotective agents on peripheral nerve regeneration assayed by time-lapse imaging in vivo.
    J Neurosci. 2003 Dec 10;23(36):11479-88 PMID: 14673013
  24. Neurite retraction and regrowth regulated by membrane retrieval, membrane supply, and actin dynamics.
    Brain Res. 2009 Jan 28;1251:65-79 PMID: 19022228
  25. PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration.
    Nat Neurosci. 2004 Mar;7(3):261-8 PMID: 14770187
  26. A study of degeneration and regeneration in the divided rat sciatic nerve based on electron microscopy. II. The development of the "regenerating unit".
    Z Zellforsch Mikrosk Anat. 1972;124(1):103-30 PMID: 5011137
  27. Posttranslational modifications of tubulin and the polarized transport of kinesin-1 in neurons.
    Mol Biol Cell. 2010 Feb 15;21(4):572-83 PMID: 20032309
  28. Axonal regeneration in the adult lamprey spinal cord.
    J Comp Neurol. 1991 Apr 15;306(3):409-16 PMID: 1865001
  29. Genetic dissection of axon regeneration.
    Curr Opin Neurobiol. 2011 Feb;21(1):189-96 PMID: 20832288
  30. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure.
    Exp Neurol. 2008 Feb;209(2):294-301 PMID: 17617407
  31. Axonal regeneration in dorsal spinal roots is accelerated by peripheral axonal transection.
    Brain Res. 1987 May 19;411(2):406-8 PMID: 2440520
  32. Plasticity of polarization: changing dendrites into axons in neurons integrated in neuronal circuits.
    Curr Biol. 2008 Jul 8;18(13):992-1000 PMID: 18595703
  33. Kinesin superfamily motor proteins and intracellular transport.
    Nat Rev Mol Cell Biol. 2009 Oct;10(10):682-96 PMID: 19773780
  34. Neural plasticity after peripheral nerve injury and regeneration.
    Prog Neurobiol. 2007 Jul;82(4):163-201 PMID: 17643733
  35. Vesicle-mediated restoration of a plasmalemmal barrier in severed axons.
    News Physiol Sci. 2003 Jun;18:115-8 PMID: 12750447
  36. Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration.
    J Neurosci. 2005 Jan 12;25(2):331-42 PMID: 15647476
  37. Local self-assembly mechanisms underlie the differential transformation of the proximal and distal cut axonal ends into functional and aberrant growth cones.
    J Comp Neurol. 2008 Mar 1;507(1):1019-30 PMID: 18092341
  38. Local calcium-dependent mechanisms determine whether a cut axonal end assembles a retarded endbulb or competent growth cone.
    Exp Neurol. 2009 Sep;219(1):112-25 PMID: 19442660
  39. Lipid dynamics in neurons.
    Biochem Soc Trans. 2006 Jun;34(Pt 3):399-403 PMID: 16709172
  40. Inhibition of regeneration of severed axons in the spinal cord.
    Exp Neurol. 1980 Jul;69(1):209-11 PMID: 7389848
  41. Axotomy induces a transient and localized elevation of the free intracellular calcium concentration to the millimolar range.
    J Neurophysiol. 1995 Dec;74(6):2625-37 PMID: 8747220
  42. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury.
    Science. 2011 Feb 18;331(6019):928-31 PMID: 21273450
  43. Extent and mechanism of sealing in transected giant axons of squid and earthworms.
    J Neurosci. 1994 Nov;14(11 Pt 1):6638-51 PMID: 7965066
  44. Studies on the development and behavior of the dystrophic growth cone, the hallmark of regeneration failure, in an in vitro model of the glial scar and after spinal cord injury.
    J Neurosci. 2004 Jul 21;24(29):6531-9 PMID: 15269264
  45. Axon regeneration requires a conserved MAP kinase pathway.
    Science. 2009 Feb 6;323(5915):802-6 PMID: 19164707
  46. Priming events and retrograde injury signals. A new perspective on the cellular and molecular biology of nerve regeneration.
    Mol Neurobiol. 1996 Aug;13(1):61-79 PMID: 8892336
  47. How a nerve fiber repairs its cut end: involvement of phospholipase A2.
    Science. 1983 Dec 23;222(4630):1351-3 PMID: 6658457
  48. Plasmalemmal sealing of transected mammalian neurites is a gradual process mediated by Ca(2+)-regulated proteins.
    J Neurosci Res. 2003 Nov 15;74(4):541-51 PMID: 14598298
  49. Acceleration of membrane recycling by axotomy of cultured aplysia neurons.
    Neuron. 1996 Mar;16(3):641-51 PMID: 8785061
  50. Proteoglycans in the central nervous system: plasticity, regeneration and their stimulation with chondroitinase ABC.
    Restor Neurol Neurosci. 2008;26(2-3):131-45 PMID: 18820407
  51. Disorganized microtubules underlie the formation of retraction bulbs and the failure of axonal regeneration.
    J Neurosci. 2007 Aug 22;27(34):9169-80 PMID: 17715353
  52. Mixed microtubules steer dynein-driven cargo transport into dendrites.
    Curr Biol. 2010 Feb 23;20(4):290-9 PMID: 20137950
  53. Differentiated neurons retain the capacity to generate axons from dendrites.
    Curr Biol. 2000 Nov 16;10(22):1467-70 PMID: 11102812
  54. Resealing of the proximal and distal cut ends of transected axons: electrophysiological and ultrastructural analysis.
    J Neurobiol. 1993 Mar;24(3):300-16 PMID: 8492108
  55. A conditioning lesion enhances sympathetic neurite outgrowth.
    Exp Neurol. 2005 Aug;194(2):432-43 PMID: 16022869
  56. Spatiotemporal distribution of Ca2+ following axotomy and throughout the recovery process of cultured Aplysia neurons.
    Eur J Neurosci. 1993 Jun 1;5(6):657-68 PMID: 8261139
  57. Calcium dynamics: analyzing the Ca2+ regulatory network in intact cells.
    Trends Neurosci. 2008 Jan;31(1):8-19 PMID: 18054801
  58. Reevaluation of the growth-permissive substrate properties of goldfish optic nerve myelin and myelin proteins.
    J Neurosci. 1995 Nov;15(11):7500-8 PMID: 7472501
  59. Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity.
    Neuron. 2002 Feb 28;33(5):689-702 PMID: 11879647
  60. Experimentally induced alteration in the polarity of developing neurons.
    Nature. 1987 Nov 19-25;330(6145):254-6 PMID: 3313064
  61. Axonal mRNA in uninjured and regenerating cortical mammalian axons.
    J Neurosci. 2009 Apr 15;29(15):4697-707 PMID: 19369540
  62. Semaphorins in axon regeneration: developmental guidance molecules gone wrong?
    Philos Trans R Soc Lond B Biol Sci. 2006 Sep 29;361(1473):1499-511 PMID: 16939971
  63. The fine structure of stumps of transected nerve fibers in subserial sections.
    J Neurol Sci. 1980 Jan;44(2-3):181-203 PMID: 7188775
  64. Caenorhabditis elegans neuronal regeneration is influenced by life stage, ephrin signaling, and synaptic branching.
    Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15132-7 PMID: 17848506
  65. Novel form of growth cone motility involving site-directed actin filament assembly.
    Nature. 1992 Jun 11;357(6378):515-8 PMID: 1608453
  66. Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase.
    J Neurosci. 2010 Mar 3;30(9):3175-83 PMID: 20203177
  67. How hard is the CNS hardware?
    Nat Neurosci. 2010 Dec;13(12):1444-6 PMID: 21102566
  68. Membrane resealing in cultured rat septal neurons after neurite transection: evidence for enhancement by Ca(2+)-triggered protease activity and cytoskeletal disassembly.
    J Neurosci. 1991 Oct;11(10):3257-67 PMID: 1941083
  69. RNA trafficking in axons.
    Traffic. 2006 May;7(5):508-15 PMID: 16643274
  70. Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels.
    J Neurosci. 1995 Oct;15(10):6445-52 PMID: 7472407
  71. In vivo imaging of axonal degeneration and regeneration in the injured spinal cord.
    Nat Med. 2005 May;11(5):572-7 PMID: 15821747
  72. Coordination of actin filament and microtubule dynamics during neurite outgrowth.
    Dev Cell. 2008 Jul;15(1):146-62 PMID: 18606148
  73. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury.
    Neuron. 1999 May;23(1):83-91 PMID: 10402195
  74. Matrix metalloproteinase inhibition enhances the rate of nerve regeneration in vivo by promoting dedifferentiation and mitosis of supporting schwann cells.
    J Neuropathol Exp Neurol. 2010 Apr;69(4):386-95 PMID: 20448483
  75. An emergency response team for membrane repair.
    Nat Rev Mol Cell Biol. 2005 Jun;6(6):499-505 PMID: 15928713
  76. Establishment of neuronal polarity: lessons from cultured hippocampal neurons.
    Curr Opin Neurobiol. 2000 Oct;10(5):574-81 PMID: 11084319
  77. Dynamics of axonal microtubules regulate the topology of new membrane insertion into the growing neurites.
    J Cell Biol. 1998 Nov 16;143(4):1077-86 PMID: 9817763
  78. Calcium entry through L-type calcium channels is essential for neurite regeneration in cultured sympathetic neurons.
    J Neurotrauma. 2004 Mar;21(3):357-74 PMID: 15115609
  79. Early changes in gene expression in the dorsal root ganglia after transection of the sciatic nerve; effects of amphiregulin and PAI-1 on regeneration.
    Brain Res Mol Brain Res. 2005 May 20;136(1-2):65-74 PMID: 15893588
  80. Transcriptome analysis of embryonic and adult sensory axons reveals changes in mRNA repertoire localization.
    RNA. 2011 Jan;17(1):85-98 PMID: 21098654
  81. Calcium concentration dynamics produced by synaptic activation of CA1 hippocampal pyramidal cells.
    J Neurosci. 1992 Nov;12(11):4202-23 PMID: 1359030
  82. Tubulin tyrosination navigates the kinesin-1 motor domain to axons.
    Nat Neurosci. 2009 May;12(5):559-67 PMID: 19377471
  83. The economics of neurite outgrowth--the addition of new membrane to growing axons.
    Trends Neurosci. 1996 Apr;19(4):144-9 PMID: 8658598
  84. Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury.
    J Neurosci. 2009 Oct 21;29(42):13242-54 PMID: 19846712
  85. The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury.
    Exp Neurol. 2008 Feb;209(2):321-32 PMID: 17720160
  86. Taxol facilitates axon regeneration in the mature CNS.
    J Neurosci. 2011 Feb 16;31(7):2688-99 PMID: 21325537
  87. Cytoskeletal and morphological alterations underlying axonal sprouting after localized transection of cortical neuron axons in vitro.
    J Neurosci. 2003 May 1;23(9):3715-25 PMID: 12736342
  88. The downregulation of GAP-43 is not responsible for the failure of regeneration in freeze-killed nerve grafts in the rat.
    Exp Neurol. 1994 Oct;129(2):311-20 PMID: 7957743
  89. Peripheral injury enhances central regeneration of primary sensory neurones.
    Nature. 1984 Jun 28-Jul 4;309(5971):791-3 PMID: 6204205
  90. 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. 2005 Apr;21(8):2051-62 PMID: 15869501
  91. Microtubule reassembly from nucleating fragments during the regrowth of amputated neurites.
    J Cell Biol. 1986 Sep;103(3):917-27 PMID: 3745275
  92. Survival of isolated axonal segments in culture: morphological, ultrastructural, and physiological analysis.
    Exp Neurol. 1993 Aug;122(2):295-310 PMID: 8405266
  93. Mechanisms of acute axonal degeneration in the optic nerve in vivo.
    Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):6064-9 PMID: 20231460
  94. betaIV-spectrin forms a diffusion barrier against L1CAM at the axon initial segment.
    Mol Cell Neurosci. 2007 Mar;34(3):422-30 PMID: 17223356
  95. Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways.
    Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10738-43 PMID: 21670305
  96. Experimental observations on the development of polarity by hippocampal neurons in culture.
    J Cell Biol. 1989 Apr;108(4):1507-16 PMID: 2925793
  97. On-line confocal imaging of the events leading to structural dedifferentiation of an axonal segment into a growth cone after axotomy.
    J Comp Neurol. 2006 Feb 10;494(5):705-20 PMID: 16374810
  98. Movement and extension of isolated growth cones.
    Exp Cell Res. 1977 Jan;104(1):55-62 PMID: 556695
  99. Impairment of protein trafficking upon overexpression and mutation of optineurin.
    PLoS One. 2010 Jul 12;5(7):e11547 PMID: 20634958
  100. Real time imaging of calcium-induced localized proteolytic activity after axotomy and its relation to growth cone formation.
    Neuron. 1998 Jun;20(6):1123-35 PMID: 9655501
  101. Transcriptional upregulation of SCG10 and CAP-23 is correlated with regeneration of the axons of peripheral and central neurons in vivo.
    Mol Cell Neurosci. 2002 Aug;20(4):595-615 PMID: 12213442
Article Info
Journal
Nature reviews. Neuroscience
Abbr.
Nat Rev Neurosci
ISSN
1471-0048
DOI
10.1038/nrn3176
Published
2012-02-15
Epub
2012-00-15
Pages
183-93
Language
English
Region
England
NLM ID
100962781
Subset
IM
Grants
Medical Research Council · G1000864 · United Kingdom
External Links
PubMed source DOI: 10.1038/nrn3176 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2