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regulators, including Rheb and insulin growth factor 1 (IGF1), which could
act as a “feed-forward” mechanism to further potentiate mTOR activation
and axon growth. Interestingly, deleting PTEN and/or SOCS3 leads to
reduction of KLF4, a transcription factor known to impede axon
regeneration (
Moore et al., 2009
), and an upregulation of KLF6, a
member of the same gene family known to facilitate axon regeneration
(
Moore et al., 2009
). Thus, axon regeneration induced after manipulating
PTEN and SOCS3 may in part be due to their ability to shift the balance
of KLF genes toward those that favor axon growth. Despite these
insights, however, the underlying mechanisms of synergistic axon
regeneration after modifying multiple genes remain largely unknown and
require further investigation.
5. SUMMARY AND PERSPECTIVES
Recent progress in promoting robust regeneration of mammalian
CNS axons using genetic manipulation of neurons supports the notion that
activating intrinsic growth programs is critical to reverse axon regeneration
failure. Depleting PTEN in adult CNS neurons enhances axon regrowth, an
effect that could be further potentiated by simultaneously targeting SOCS3
or other growth-enhancing factors (
Kurimoto et al., 2010; Park et al., 2008;
Sun et al., 2011
). The pursuit of robust and sustained regeneration of injured
CNS axons raises several important questions. First, what are the main
molecular mechanisms underlying the synergistic effects induced after
inactivating PTEN and SOCS3 in neurons? Deciphering the mechanisms
underlying this form of axon regeneration may further extend our
understanding of axon regeneration failure. PTEN and SOCS3 are two
signaling suppressors whose perturbation is likely to affect myriad
downstream effectors. Accordingly, a wide range of cellular processes
could be activated including cytoskeleton dynamics, growth cone
formation, axonal transport, and axon extension. These events are key to
successful axon regeneration. PTEN and SOCS3 deletion in RGCs
results in hyperactivation of mTOR and STAT3, and preventing
activation of these two molecules attenuates axon regeneration (
Park,
Liu, Hu, Kanter, & He, 2010; Park et al., 2008; Smith et al., 2009; Sun
et al., 2011
). Thus, it is conceivable that while mTOR may determine
the competence of axon regeneration, gp130/STAT3 dependent signals
likely represent injury signals that could switch on or off the regenerative
program (
Fig. 7.3
). Elucidating the genetic interplay between signaling
