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The Journal of Neuroscience, January 12, 2005, 25(2):331-342; doi:10.1523/JNEUROSCI.3073-04.2005

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Development/Plasticity/Repair
Axonal Protein Synthesis and Degradation Are Necessary for Efficient Growth Cone Regeneration

Poonam Verma,¹ Sabrina Chierzi,¹ Amanda M. Codd,² Douglas S. Campbell,³ Ronald L. Meyer,⁴ Christine E. Holt,³ and James W. Fawcett¹

¹Cambridge University Centre for Brain Repair, Cambridge CB2 2PY, United Kingdom, ²University of California, San Francisco, San Francisco, California 94143, ³Department of Anatomy, University of Cambridge, Cambridge CB2 3DY, United Kingdom, and ⁴Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697

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.

Key words: growth cone formation; axotomy; local protein synthesis; proteasome-mediated degradation; conditioning lesion; axon regeneration

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Received March 15, 2004; revised November 4, 2004; accepted November 12, 2004.

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