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  • Review Article
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Assembly of a new growth cone after axotomy: the precursor to axon regeneration

Nature Reviews Neuroscience volume 13, pages 183–193 (2012)Cite this article

Subjects

Key Points

  • Before a cut axon can attempt to grow, it first has to assemble a new growth cone at its tip.

  • The mechanism leading to the assembly of a new growth cone includes the following events: membrane seal formation; calcium influx; activation of kinases, phosphatases and proteases; local restructuring of the cytoskeleton; accumulation of Golgi-derived vesicles; and fusion of such vesicles with the plasma membrane. These events are supported by concurrent local protein translation and anterograde transport of proteins that are in transit in the axon, but are probably not supported by new protein synthesis in the cell body.

  • During the formation of a frustrated growth cone or end bulb, vesicles that accumulate at the cut end of an axon fail to fuse with the plasma membrane, and the microtubules point their tips in a retrograde direction. End bulb formation can result from the failure of any one of the events described above.

  • In the future, it may be possible to prevent the failure of growth cone regeneration by stabilizing microtubules with nanomolar concentrations of taxol; by enhancing or enabling the transport of protein translation machinery (for example, mRNA and ribosomes) from the cell body to the site of injury through changing the 'filtering' properties of the axon's initial segment; or by facilitating the fusion of accumulating vesicles with the end bulb membrane.

  • The intrinsic difference in growth cone regenerative capability that is observed between mammalian CNS and PNS axons may be due to differences in the extent of depolymerization of the cytoskeleton after axotomy, signalling pathways, transport of growth-related molecules and/or the propensity for local protein translation.

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.

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Figure 1: Key events in the transformation of the proximal tip of a cut axon into a growth cone.
Figure 2: Formation of a retraction bulb and its rescue.
Figure 3: Molecular events in growth cone regeneration.

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Acknowledgements

This Review was written as a result of a meeting sponsored by the UK Academic Study Group and the Institute of Advanced Studies of the Hebrew University of Jerusalem, Israel. The laboratory of M.E.S is supported by grants from The Israel Science Foundation, The Israel Ministry of Health, The United States–Israel Binational Science Foundation, the European Commission and the Charles E. Smith Family and Professor Joel Elkes Laboratory for Collaborative Research in Psychobiology. The laboratory of F.B. is supported by the Deutsches Zentrum für Neurodegenerative Erkrankungen, the Deutsche Forschungsgemeinschaft, the International Foundation for Research in Paraplegia and the Human Frontier Science Program. J.W.F. is supported by the UK Medical Research Council, Engineering and Physical Sciences Research Council, European Union Framework 7 Programme Spinal Cord Repair, Plasticise and Angioscaff, Henry Smith Charity, Christopher and Dana Reeve Foundation, and the UK National Institute of Health Research Cambridge Biomedical Research Centre.

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Authors and Affiliations

  1. Axonal Growth and Regeneration, German Center for Neurodegenerative Disease, Ludwig-Erhard-Allee 2, Bonn, 53175, Germany

    Frank Bradke

  2. Department of Clinical Neurosciences, Cambridge University Centre for Brain Repair, Robinson Way, Cambridge, CB2 0PY, UK

    James W. Fawcett

  3. Department of Neurobiology, Life Science Institute, the Hebrew University of Jerusalem, Jerusalem, 91904, Israel

    Micha E. Spira

Authors
  1. Frank Bradke
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  2. James W. Fawcett
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  3. Micha E. Spira
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Corresponding author

Correspondence to James W. Fawcett.

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Competing interests

James Fawcett is a paid consultant for Acorda Therapeutics, Novartis and Covidien. Frank Bradke and Micha E. Spira declare no competing financial interests.

Supplementary information

Supplementary Information Figure S1

Formation of vesicles traps by microtubules restructuring after axotomy. (PDF 5338 kb)

Supplementary Information S2 (movie)

Uniform microtubule plus end orientation in a control axon of a cultured Aplysia californica neuron. (AVI 1923 kb)

Supplementary Information S2 (PDF 125 kb)

Supplementary Information S3 (movie)

The formation of microtubule-based vesicle traps after axotomy. (AVI 5107 kb)

Supplementary Information (PDF 117 kb)

Supplementary Information S4 (movie)

Accumulation of organelles in the microtubule-based vesicle traps after axotomy. (AVI 4660 kb)

Supplementary Information (PDF 120 kb)

Supplementary Information S5 (movie)

The spatiotemporal relationships between the formation of microtubule-based vesicle traps and the accumulation of organelles. (AVI 7908 kb)

Supplementary Information (PDF 119 kb)

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FURTHER INFORMATION

Frank Bradke's homepage

Glossary

Local protein translation

Mammalian peripheral nervous system axons and axons in many invertebrate species contain ribosomes, messenger RNAs and a Golgi apparatus or equivalent. In such axons, proteins can be synthesized in the axon tip, and if local translation is prevented, the regeneration of a cut axon is inhibited.

Taxol

Taxol is a compound that at low concentrations promotes the polymerization of tubulin into microtubules and stabilizes microtubules against depolymerization, and hence may promote axon growth over inhibitory substrates.

The conditioning response

A severed peripheral nervous system axon will begin to regenerate after a few hours. If the same axon is cut again 2 or more days later, the speed of axon regeneration increases. This phenomenon is known as the conditioning response.

Axon initial segment

The axon initial segment is the part of the axon that is closest to the cell body and is the point of initiation for action potentials. It may also act as a selective transport filter for some types of axonal cargo.

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Bradke, F., Fawcett, J. & Spira, M. Assembly of a new growth cone after axotomy: the precursor to axon regeneration. Nat Rev Neurosci 13, 183–193 (2012). https://doi.org/10.1038/nrn3176

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