Biology Reference
In-Depth Information
2.3. Promoting cytoskeletal remodeling and axonal transport
Axon growth depends on the forward movement of the growth cone, which
is composed of a central region containing mainly microtubules and periph-
eral region enriched with actin cytoskeleton. In response to various environ-
mental signals, developing neurons undergo dynamic morphological
changes through orchestrated remodeling of the cytoskeleton. In this
regard, the growth cone undergoes reorganization of the cytoskeleton
including actin dynamics and microtubule stabilization, which is essential
for efficient axon extension. More importantly, coordinated remodeling
of the cytoskeleton is also required for axon regrowth after injury. The piv-
otal role of such remodeling in the control of axon regeneration is under-
scored by the observation that regenerative growth after axotomy in the
mature CNS can be enhanced through direct stabilization of microtubule
by taxol (
Hellal et al., 2011; Sengottuvel, Leibinger, Pfreimer, Andreadaki,
& Fischer, 2011
). Interestingly, Cdk5 orchestrates efficient cytoskeletal
remodeling through phosphorylation of a myriad of actin and microtubule
regulators, which contribute to axon initiation, elongation, and regeneration.
2.3.1 Cdk5 as a modulator of actin dynamics
Actin dynamics plays important roles in axon specification and growth. For
example, local actin depolymerization in the growth cone of a single neurite
is sufficient to specify its axon identity (
Bradke & Dotti, 1999
).
In addition,
Rho GTPases, including RhoA, Rac1, and Cdc42, have emerged as critical
players of actin dynamics through modulation of actin-binding proteins.
The activity of Rho GTPases is positively regulated by guanine nucleotide
exchange factors, and negatively regulated by GTPase activating proteins
(GAPs). Interestingly, these Rho GTPases elicit opposite effects on axon
growth, namely, while RhoA activation mostly results in growth cone
collapse, Rac1 and Cdc42 are dedicated to axon outgrowth and extension
(
Dillon & Goda, 2005
).
A plethora of regulators and effectors of Rho GTPases have been
documented as substrates of Cdk5. Among multiple upstream molecules
of Rho GTPases, Cdk5 phosphorylates p27
kip1
(
Kawauchi, Chihama,
Nabeshima, & Hoshino, 2006
), RasGRF1 (
Kesavapany et al., 2006
),
RasGRF2 (
Kesavapany et al., 2004
), kalirin-7 (
Xin et al., 2008
), and
ephexin 1 (
Fu et al., 2007
). Cdk5 also regulates actin organization through
phosphorylation of Rho GTPase effectors such as Pak1 (
Nikolic, Chou, Lu,
Mayer, & Tsai, 1998; Rashid, Banerjee, & Nikolic, 2001
) and WAVE1
