The control of growth-cone behaviour by axon guidance cues involves regulating local protein synthesis and axonal transport; however, the precise molecular mechanism is still unknown. Reporting in the Journal of Neuroscience, Li and colleagues found that semaphorin3A (SEMA3A) induces axonal transport by activating a translation-initiation factor at the growth cone and that the process depends on the tyrosine kinase FYN and the cyclin-dependent kinase 5 (CDK5).

SEMA3A is a secreted guidance cue that is strongly repulsive to axons from dorsal root ganglia (DRG) and sympathetic neurons. Signalling by SEMA3A requires the activity of both FYN and CDK5, as inhibitors of either molecule can block the collapsing effect of SEMA3A on growth cones. In this study, the authors assessed whether SEMA3A-elicited axonal transport in cultured DRG neurons also requires FYN and CDK5 by using a video-enhanced contrast differential interference video camera system. They found that inhibitors of either FYN or CDK5 abolished the ability of SEMA3A to induce anterograde and retrograde axonal transport. Similarly, SEMA3A-induced axonal transport is also attenuated in DRG neurons from mice deficient in either Fyn or p35, an activator of CDK5.

The authors then measured SEMA3A-elicited axonal transport in the presence of inhibitors of either protein synthesis or degradation. Inhibition of protein synthesis suppressed axonal transport and SEMA3A-induced growth-cone collapse, but inhibition of degradation did not.

The signalling cascades that stimulate axonal transport can occur either locally, at the growth cone, or globally, involving the cell body. To differentiate between these possibilities, the authors performed similar assays using neurites that were severed from the soma. They showed that growth cones from isolated neurites also collapsed in response to SEMA3A and that acceleration of axonal transport was similar to that in intact neurons. Furthermore, inhibitors of FYN, CDK5 and protein synthesis could also block SEMA3A-induced axonal transport in isolated neurites. Therefore, activation of local signalling cascades and local protein synthesis is responsible for SEMA3A-induced axonal transport.

The authors then attempted to pinpoint which translation factors are involved. They found that eukaryotic translation-initiation factor 4E (eIF-4E) at the growth cone was phosphorylated in response to SEMA3A — an effect that was diminished by inhibitors of either FYN or CDK5. Similarly, SEMA3A-induced phosphorylation of eIF-4E was also compromised in DRG neurons from Fyn−/− and p35−/− mice.

The study suggests an interesting link between the functions of FYN and CDK5 and local activation of a translation-initiation factor at the growth cone in response to guidance cues. Further analysis is necessary to delineate the signalling mechanisms and to identify newly synthesized target proteins that are responsible for initiating downstream molecular events in axon guidance and neural plasticity.