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Interestingly, Cdk5 is implicated in local protein synthesis mediated by
semaphorin 3A-induced local activation of eukaryotic translation initiation
factor 4E (eIF-4E) in the growth cone. In particular, although semaphorin
3A induced phosphorylation and activation of eIF-4E in the growth cones,
the induced phosphorylation of eIF-4E was diminished by pharmacological
inhibitor of Cdk5 or genetic ablation of p35 in DRG neurons (
Li et al.,
2004
). One limitation of this study is that Cdk5 was inhibited globally in
both soma and axon, and thus renders the axon-specific role of Cdk5 obscure
in this event. In addition, the exact underlying mechanism of Cdk5 in
semaphorin 3A-induced phosphorylation remains elusive. Additional stud-
ies are needed to delineate the axon-specific role of Cdk5 by selective
knockdown of axonal Cdk5, as well as to identify the downstream signaling
pathways.
2.4.3 APC/Cdh1 and protein degradation
In addition to protein synthesis, regulation of protein expression via selective
degradation is important for axon initiation and growth. For instance, selec-
tive enrichment of the activated protein kinase AKT in a single neurite that
destined to become axon, accompanied with degradation of AKT in other
processes is critical for asymmetric distribution of the protein and axon growth
(
Yan, Guo, & Wang, 2006
). Additional work has revealed the inhibitory
function of the anaphase-promoting complex (APC), an E3 ubiquitin ligase
complex, and its activator protein Cdh1 in axon growth. APC/Cdh1 com-
plex is originally identified to be important for degradation of cell cycle pro-
teins. The first hint about a potential role of APC/Cdh1 in axon growth was
provided by an earlier study reporting the presence of active APC/Cdh1 in
the nucleus in postmitotic neurons, and recent studies have advanced this ob-
servation by discovering that knockdown of Cdh1 increased axon growth in
primary cerebellar granule neurons (
Konishi, Stegmuller, Matsuda, Bonni, &
Bonni, 2004
). These results provide insight into the cell-autonomous function
of APC/Cdh1 in antagonizing axon extension, presumably through destabi-
lization of molecules necessary for the axon growth. In concordance with this
notion, follow-up studies demonstrated that APC/Cdh1 inhibit axon growth
by destabilizing at least two transcriptional factors, Id2 and SnoN. On one
hand, APC/Cdh1 targets Id2 for degradation through a destruction box. Sta-
bilization of Id2 not only enhances the axon growth in developing neurons
but also overcomes the myelin inhibitory effects of axon regeneration in in-
jured neurons (
Lasorella et al., 2006
). On the other hand, APC/Cdh1 facil-
itates the degradation of SnoN, which leads to impaired axon extension and
