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suggesting that these phosphorylation events regulate its association to
dynein. Indeed, inhibition of Cdk5 activity alters the localization of
NUDEL and its affinity to the dynein complex, resulting in axonal
swellings (
Niethammer et al., 2000
). Similar varicose phenotype has been
observed in
Drosophila
mutants with defective axonal transport (
Goldstein
& Yang, 2000
). These data collectively underscores the importance of
Cdk5 in regulating the transport of membrane-bound vesicles during
axon development. Nevertheless, whether kinesin- and dynein-based
axonal transport also contributes to axon regeneration after injury awaits
further investigation.
2.4. Safeguarding protein translation and boycotting
degradation
Axon growth under developmental and regenerative conditions relies on
temporal and spatial regulation of protein expression. Other than transcrip-
tion, protein expression is determined by the translation of mRNA into
protein as well as proteasomal machinery which leads to protein degradation.
2.4.1 PTEN/mTOR/S6K1 and global protein translation
In response to stimulating signals, protein synthesis mediated by mTOR/S6
kinase 1 (S6K1) signaling pathway plays leading roles in developmental pro-
grams that direct axon morphogenesis. For example, mTOR is required for
both attractive response caused by chemoattractant and repulsive turning
triggered by chemorepellents. Application of mTOR inhibitor, rapamycin,
suppresses netrin 1-induced directional axon growth and semaphorin
3A-induced growth cone collapse in cultured
Xenopus
RGCs (
Campbell
& Holt, 2001
). While mTOR is activated by upstream molecules PI3K/
AKT, mTOR is negatively regulated by phosphatase and tensin homolog
(PTEN) (
Hay & Sonenberg, 2004
). By antagonizing PI3K/AKT, PTEN
acts as a negative regulator of axon growth during axon development.
In particular, overexpressing PTEN impaired axon formation, whereas
shRNA-mediated knockdown of PTEN expression resulted in the formation
of multiple axons in cultured hippocampal neurons (
Jiang et al., 2005
).
In the adulthood, PTEN and mTOR continue to play pivotal roles in
the regulation of regenerative growth ability after axotomy. Recent evidence
demonstrated that targeted deletion of PTEN not only protects injured neu-
rons from cell death, but also promotes robust axon regeneration after optic
nerve damage (
Park et al., 2008
). Among various downstream targets of
PTEN, mTOR-dependent protein translation is of central importance.
