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patterning in parallel fibers of cerebellar granule neurons. This phenotype can
be recapitulated in the primary hippocampal and cortical neurons (
Stegmuller
et al., 2006
), underscoring the importance of this pathway in axon
morphogenesis. Taken together, these data suggests that neuronal APC/
Cdh1 controls programs of gene expression that are crucial for both develop-
mental and regenerative axon growth.
Interestingly, recent studies identified Cdh1 as a novel substrate of Cdk5
(
Maestre, Delgado-Esteban, Gomez-Sanchez, Bolanos, & Almeida, 2008
).
Specifically, Cdk5-mediated phosphorylation of Cdh1 at Ser40, Thr121,
and Ser163 dissociates Cdh1 from APC, thus suppressing the activity of
APC/Cdh1. Indeed, Cdk5 has been found to prevent APC/Cdh1-
mediated degradation of signaling molecules, such as cyclin B1 (
Maestre
et al., 2008
). Further evidence has implicated the functional roles of
Cdk5-mediated phosphorylation in the regulation of axon growth via
inhibition of APC/Cdh1 function (
Huynh, Stegmuller, Litterman, &
Bonni, 2009
). These observations collectively highlight the inhibition of
APC/Cdh1 activity by maintaining Cdk5-mediated phosphorylation as a
promising approach for promoting axon regeneration.
2.5. Other Cdk5-mediated mechanisms
Apart from cytoskeletal and translational regulations, other Cdk5-mediated
mechanisms have been implicated in axon growth ability under both devel-
opmental and regenerative conditions. Signaling mechanisms including
gene transcription and membrane trafficking will be discussed here.
2.5.1 Nuclear function of Cdk5
Axon growth and regeneration is controlled by various transcriptional
factors. STAT3 is one of the transcriptional factors implicated in axon
growth and regeneration. In developing hippocampal neurons, knock-
down of STAT3 results in decreased BDNF-induced axon outgrowth
(
Ng, Cheung, & Ip, 2006
), suggesting a functional involvement of
STAT3 in normal axon growth. In the adult nervous system, STAT3
continues to play an important role in axon regeneration following
PNS and CNS injury, since regenerative axon growth depends on
gp130 receptor and downstream JAK2/STAT3 signaling. Application
of JAK2/STAT3 inhibitors not only abolishes axon regeneration, but also
reduces the expression of regeneration-associated protein GAP-43 (
Qiu,
Cafferty, McMahon, & Thompson, 2005
), indicating a pivotal role of
STAT3 in the conditioning effect of a peripheral lesion. A recent study
