Biology Reference
In-Depth Information
reported the presence of PTEN in the axon compartment of DRG growth
cones during axon growth, and following exposure to Sema3A, PTEN
accumulates rapidly at the growth cone membrane. Further, Sema3A
suppresses PI3K signaling and leads to activation of GSK3, a sequence of
event dependent on the phosphatase activity of PTEN. These findings
demonstrate the role of axonal PTEN in regulating GSK3 signaling in
response to growth-inhibitory cues and highlighted the importance of
subcellular localization of PTEN to regulate growth cone dynamic
(
Chadborn et al., 2006
). Continuous addition of microtubules at the
growth cone is a key for successful axon regeneration, a process that is
tightly controlled by coordinated regulation of microtubule dynamics and
actin rearrangement in the growth cone. Many microtubule binding
proteins (MBPs) including collapsin response mediator protein 2
(CRMP2), adenomatous polyposis coli (APC), Tau, and MAP 1b are
known to regulate this process in response to various extracellular stimuli.
GSK3 is regarded as a key mediator that integrates extracellular signals and
MBP to control axon growth by modulating microtubule dynamics and
stability (
Hur & Zhou, 2010
). Phosphorylation of these MBPs by GSK3
eliminates their ability to associate with microtubules. Conversely,
inhibition of GSK3 facilitates the binding of CRMP2 to tubulin dimers and
promotes axon growth by enhancing microtubule assembly in the growth
cone (
Fukata et al., 2002; Yoshimura et al., 2005
). Several studies have
reported that inactivation of GSK3 promotes axon growth, suggesting that
the level of GSK3 activity and subcellular localization of inactivated GSK3
may influence the overall growth cone behavior.
Hur et al. (2011)
recently
reported the role of cytoplasmic linker-associated protein (CLASP, a
microtubule stabilizing protein) in transducing GSK3 activity levels to
differentially regulate axon growth (i.e., either inhibit or promote growth)
by coordinating the stability and arrangement of growth cone microtubules.
In addition to its action on microtubule polymerization and assembly,
GSK3 is known to regulate the activity (or degradation) of several
transcription factors known to affect axon regeneration. These include
AP1, p53, SMAD, NFAT (nuclear factor activated T-cells), and NF
k
B.
Several reviews have recently described in greater detail the potential
mechanisms and downstream targets of GSK3 in regulating the process of
growth cone formation and axon growth (
Kim, Hur, et al., 2011; Liu et al.,
2012
). Overall, considering its potent roles in growth cone formation and
axon extension, GSK3 may contribute to downstream PTEN effects on
axon regeneration.
