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steering directions for elongating axons, it is not surprising that the final
target of most if not all guidance signaling pathways is the modulation of
the cytoskeleton, with actin being one of the primary targets ( Dent et al.,
2011 ). Guidance cue mediated regulation of actin-binding protein activity
has been the predominant model used to explain localized actin polymer-
ization within growth cones ( Pak et al., 2008 ), but the high profile finding
that β-actin can also be locally synthesized within growth cones likely adds
another layer of complexity to that model.
Although we have found that β- and γ-actin proteins colocalize in
growth cones ( Cheever et al., 2012 ), only β-actin transcripts have been
detected in growth cones to date ( Bassell et al., 1998 ). Local translation of
β-actin may thus subtly alter the composition of growth cone actin with
important functional consequences. Interestingly, treatment with antisense
oligonucleotides targeted to the β-actin mRNA zipcode sequence abro-
gated the guidance cue-induced enrichment of β-actin within growth
cones, suggesting that a zipcode-ZBP1 mechanism may be involved
( Zhang et al., 2001 ). Expression of a full length β-actin construct fused to
GFP showed a similar neurotrophin-dependent increase in GFP localiza-
tion within growth cones, while constructs lacking the zipcode sequence
showed no enrichment of GFP localization. Since ZBP1 is known to be
expressed in developing neurons ( Zhang et al., 2001 ), the ZBP1-mediated
localization and local translation of β-actin mRNA within growth cones
may thus be an important mechanism in mediating actin reorganization and
dynamics during growth cone guidance.
In 2006, two back-to-back studies published by independent groups
using cultured Xenopus neuron systems tested the hypothesis that the local
translation of β-actin is critical for growth cone turning and guidance. In
the first study, β-actin mRNA and the Xenopus homolog of ZBP3/IMP3,
Vg1 RBP, were found to colocalize within retinal neuron growth cones
( Leung et al., 2006 ). Interestingly, the relative levels ofVg1 RBP and β-actin
within growth cones could be enhanced upon exposure to the attractive
guidance cue netrin-1. This localization appeared to result in increased local
translation of β-actin mRNA, as netrin-1 treatment induced a significant
increase in the amount of β-actin protein found within the growth cone
by immunofluorescence. The increase in β-actin protein levels was blocked
by protein synthesis inhibitors, and more interestingly, by antisense mor-
pholinos directed at the start codon of β-actin to specifically block trans-
lation. Further evidence for the local translation of β-actin was presented
when axons expressing a photoconvertible Kaede fluorescent protein fused
to the 3′ UTR of β-actin were severed from their cell bodies. Following
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