Biology Reference
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regeneration in various experimental paradigms of CNS injury (
Sun & He,
2010
). Although it is possible that the extracellular inhibitors that are critical
for the axon regeneration await further identification, it is more likely that
the adult CNS neurons lose their intrinsic axon growth ability during
the course of development. Indeed, an age-dependent loss of regenerative
ability correlates with the programmed switch of axon growth to synaptic
formation (
Liu, Tedeschi, Park, & He, 2011
). Correspondingly, a recent
screen of developmentally regulated genes identified Kr¨ppel-like factor 4
(KLF4) as a transcriptional repressor for both developmental and regenera-
tive axon growth (
Moore et al., 2009
). In addition to transcription factors,
translational regulators such as mammalian target of rapamycin (mTOR)
and cytoskeleton-associated kinases such as glycogen synthase kinase 3
b
(GSK-3
b
) represent other developmentally regulated factors that are vital
in the control of axon growth in the adult CNS (
Dill, Wang, Zhou, &
Li, 2008; Liu et al., 2010; Park et al., 2008
).
2. Cdk5 IN THE CONTROL OF AXON GROWTH
AND REGENERATION
Notably, recent evidence suggests cyclin-dependent kinase (Cdk5),
a proline-directed serine/threonine kinase, regulates axon growth and
regeneration in multiple aspects, mainly through modulating downstream
signaling cascades of extracellular factors and enabling efficient cytoskeletal
remodeling. In this chapter, we summarize the current findings on Cdk5-
mediated signaling pathways in the developmental and regenerative axon
growth, implicating the involvement of Cdk5 in axon regeneration.
2.1. Cdk5: A multifaceted neuronal kinase
Cdk5 was first identified two decades ago based on its high sequence homol-
ogy to a key regulator of cell cycle progression, Cdc2 (
Lew,Winkfein, Paudel,
& Wang, 1992; Meyerson et al., 1992
). Although Cdk5 shares
60%
sequence identity with Cdc2 and retains the main structural characteristics
of Cdks, Cdk5 is unique among the Cdk family members as the protein is
neither activated by cyclins nor playing a major role in cell cycle
regulation. Cdk5 preferentially phosphorylates substrates at the S/T sites
within a consensus motif (S/T)PX(K/H/R), where S/T represents the
phosphorylatable serine/threonine residue, P is the required proline
residue, X stands for any amino acid, and K/H/R represents a basic
residue (
Beaudette, Lew, & Wang, 1993
). Like other Cdks, monomeric
