Biology Reference
In-Depth Information
The list of Cdk5 substrates includes scaffold protein Axin (
Fang et al.,
2011
), microtubule plus-end binding protein CRMP-2 (
Yoshimura
et al., 2005
) and doublecortin DCX (
Tanaka et al., 2004
), as well as struc-
tural MAPs such as MAP1B (
Paglini et al., 1998
), and Tau (
Wada et al.,
1998
). Details of the mechanisms underlying the regulation of axon growth
by these phosphorylation events remain enigmatic, except for an unex-
pected interplay between Cdk5 and GSK-3
b
in axon formation through
an Axin signaling cascade. Through
in utero
knockdown of Axin, Fang,
and colleagues have shown that Cdk5-mediated phosphorylation of Axin
contributes to axon formation through inhibition of GSK-3
b
. In particular,
in response to neurotrophins, such as BDNF and NT3, Cdk5 is activated to
phosphorylate Axin at Thr485. Phosphorylation of Axin enhances its
interaction with GSK-3
b
and inhibits GSK-3
b
activity, thereby increasing
nonphosphorylated CRMP-2 in the growth cone. Nonphosphorylated
CRMP-2, which represents the active form, facilitates the microtubule
assembly and stabilization to promote initiation and elongation of growing
axons during development. In accordance with the inhibitory role of
GSK-3
b
in developmental axon growth, systemic administration of GSK-
3
b
inhibitor lithium promoted axon regeneration and functional recovery
in a rodent model of spinal cord injury (
Dill et al., 2008
). In light of
inhibitory regulation of GSK-3
b
by Cdk5
in vivo
, it is tempting to further
examine the functional roles of Cdk5 and Axin in axon regeneration after
CNS injury. Other MAPs, such as DCX, MAP1B, and Tau, may also play
a part, but their roles in axon regeneration remain unclear.
In addition to the regulation by various MAPs, microtubule assembly
and stabilization are also regulated by posttranslational modifications of
the basic structural unit of microtubules,
a
-tubulin. Acetylation and
deacetylation of
a
-tubulin regulate the stability of microtubule cytoskeleton
and are mediated by histone acetyltransferases and histone deacetylases
(HDACs), respectively (
Janke & Kneussel, 2010
). Notably, pharmacological
inhibition of HDAC6 promoted the axon growth of cultured neurons
grown in the presence of inhibitory substrates (i.e., MAG and CSPGs),
suggesting that deacetylases are potential targets for promoting axon
regeneration. In addition, another deacetylase sirtuin-2 (SIRT2) has also
been implicated in reversing the tubulin acetylation (
North, Marshall, Borra,
Denu, & Verdin, 2003
). SIRT2 functions as an intrinsic blocker for axon
growth and maintenance. While SIRT2 overexpression suppresses growth
cone dynamics and axon growth, SIRT2 inhibition correlates with en-
hanced tubulin stability and subsequent resistance against degenerative
