Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration

Poonam Verma, Sabrina Chierzi, Amanda M. Codd, Douglas Simon Campbell, Ronald L. Meyer, Christine E. Holt, James W. Fawcett

Research output: Contribution to journalArticle

276 Citations (Scopus)

Abstract

Axonal regeneration can occur within hours of injury, the first step being the formation of a new growth cone. For sensory and retinal axons, regenerative ability in vivo correlates with the potential to form a new growth cone after axotomy in vitro. We show that this ability to regenerate a new growth cone depends on local protein synthesis and degradation within the axon. Axotomy in vitro leads to a fourfold to sixfold increase in 3H-leucine incorporation in both neurones and axons, starting within 10 min and peaking 1 h after axotomy. Application of protein synthesis inhibitors (cycloheximide and anisomycin) to cut axons, including axons whose cell bodies were removed, or proteasome inhibitors (lactacystin and N-acetyl-Nor-Leu-Leu-Al) all result in a reduction in the proportion of transected axons able to reform growth cones. Similar inhibition of growth cone formation was observed on addition of target of rapamycin (TOR), p38 MAPK (mitogen-activated protein kinase), and caspase-3 inhibitors. Comparing retinal and sensory axons of different developmental stages, levels of ribosomal protein P0 and phosphorylated translation initiation factor are high in sensory axons, lower in embryonic axons, and absent in adult retinal axons. Conditioning lesions, which increase the regenerative ability of sensory axons, lead to increases in intra-axonal protein synthetic and degradative machinery both in vitro and in vivo. Collectively, these findings suggest that local protein synthesis and degradation, controlled by various TOR-, p38 MAPK-, and caspase-dependent pathways, underlie growth cone initiation after axotomy.

Original languageEnglish
Pages (from-to)331-342
Number of pages12
JournalJournal of Neuroscience
Volume25
Issue number2
DOIs
Publication statusPublished - 2005 Jan 12
Externally publishedYes

Fingerprint

Growth Cones
Proteolysis
Axons
Regeneration
Axotomy
p38 Mitogen-Activated Protein Kinases
Sirolimus
leucylleucine
Anisomycin
Peptide Initiation Factors
Proteasome Inhibitors
Protein Synthesis Inhibitors
Caspase Inhibitors
Mitogen-Activated Protein Kinase 3
Cycloheximide
Caspases
Leucine
Caspase 3

Keywords

  • Axon regeneration
  • Axotomy
  • Conditioning lesion
  • Growth cone formation
  • Local protein synthesis
  • Proteasome-mediated degradation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. / Verma, Poonam; Chierzi, Sabrina; Codd, Amanda M.; Campbell, Douglas Simon; Meyer, Ronald L.; Holt, Christine E.; Fawcett, James W.

In: Journal of Neuroscience, Vol. 25, No. 2, 12.01.2005, p. 331-342.

Research output: Contribution to journalArticle

Verma, Poonam ; Chierzi, Sabrina ; Codd, Amanda M. ; Campbell, Douglas Simon ; Meyer, Ronald L. ; Holt, Christine E. ; Fawcett, James W. / Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 2. pp. 331-342.
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