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To what extent this applies to CNS axons is less clear. In the cell soma,
sustained synthesis of cellular building blocks (e.g., microtubules and
integrated proteins) is also indispensable for sustained growth of injured
axons. Therefore, maintenance of mTOR and the protein translation
activity in the soma and axon, to a large extent, retains the normal cellular
activity that could support axon regrowth. mTOR may also influence axon
regeneration by mechanisms other than translational control. The activity
of several transcription factors, particularly those involved in growth,
metabolic, and biosynthetic pathways, including STAT1 and STAT3
( Kristof, Marks-Konczalik, Billings, & Moss, 2003 ), and the nuclear
receptor peroxisome proliferator-activated receptor- g ( Kim & Chen, 2004 )
are regulated by mTOR in a rapamycin-sensitive manner. mTOR has also
been shown to be critical for the optimal activation of STAT3 by CNTF
(ciliary neurotrophic factor; Yokogami, Wakisaka, Avruch, & Reeves,
2000 ), all of which suggest that the function of mTOR is not limited to
translational control, but may extend to include transcriptional regulation.
2.2.3 Local PTEN/GSK3 signaling
In addition to mTOR, other downstream targets of the PTEN pathway may
well be involved in promoting axon regrowth. This is evident by the lesser
extent of axon regeneration in the optic nerve after TSC1 deletion compared
to PTEN deletion ( Park et al., 2008 ). While PTEN deletion induces AKT
activation and many downstream targets associated with it, TSC1 lies down-
stream of PTEN, and deletion of TSC1 leads predominantly to mTOR
activation ( Fig. 7.1 ). GSK3, a major substrate of AKT has been implicated
in regulation of neurogenesis, polarization, and axon growth ( Kim, Hur,
Snider, & Zhou, 2011; Liu, Hur, & Zhou, 2012 ). GSK3 is constitutively
active in resting cells, which acts to inhibit cell signaling. Activation of
AKT in response to extracellular stimuli leads to GSK3 phosphorylation
and subsequent inactivation, thereby allowing the propagation of GSK3
signaling cascades ( Kim, Hur, et al., 2011; Liu et al., 2012 ). To date, there
is no evidence of GSK3 playing a direct role in PTEN deletion-mediated
axon regeneration; however, the existence of multiple downstream targets
of GSK3, each with potent roles in axon growth/plasticity, makes it a
strong candidate to mediate PTEN's effects on axon growth. Studies have
indicated that PTEN expressed at the axon tip has a potent role in
regulating the PI3K/AKT/GSK3 signaling pathway as well as growth cone
collapse. Growth cones in vitro collapse in the presence of semaphorin 3A
(Sema3A) ( Fan & Raper, 1995; Jackson & Eickholt, 2009 ). Chadborn et al.
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