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the JAK/STAT regulates various cellular functions, including proliferation,
growth, and immune response ( Rawlings, Rosler, & Harrison, 2004; Shuai
& Liu, 2003 ). Several studies indicate that the activation of STAT3 and
subsequent induction and changes in the neuronal gene expression are
key/important/necessary for stimulating axon regeneration in both the
PNS and CNS. This statement is supported by high levels of STAT3
activation in neurons with high regenerative capacity, reduction of axon
regeneration by pharmacologic and genetic depletion of STAT3 activity,
and increase in axon regeneration after genetically enforcing STAT3
activation. In the DRG system, a peripheral axon injury that leads to
enhanced axon regeneration is associated with concomitant activation of
STAT3 in injured neurons ( Schwaiger et al., 2000; Sheu, Kulhanek, &
Eckenstein, 2000 ). In contrast, failure of axon regrowth after a central
lesion parallels the inability of STAT3 to be activated ( Schwaiger et al.,
2000 ), pointing to distinct responsive mechanisms to axotomy in PNS
versus CNS. STAT3 activation as a consequence of the peripheral
conditioning lesion is required for the central axon regrowth ( Qiu,
Cafferty, McMahon, & Thompson, 2005 ). These results are consistent
with the hypothesis that neurons fail to respond to injury in the CNS,
while a peripheral lesion would initiate a regenerative response.
Suppressing STAT3 activity diminishes regenerative response after PNS
injury ( Bareyre et al., 2011 ), while overexpression of STAT3 enhances
neurite outgrowth in vitro and axon regeneration in vivo ( Bareyre et al.,
2011; Smith et al., 2011 ). Recent findings further defined the functional
role of STAT3 in the initiation but not elongation phase during axon
regeneration. Specifically, through real-time fluorescent imaging of
STAT3-deficient and competent axons after injury, the authors showed
that STAT3 overexpression promotes axon sprouting but not sustained
long-distance growth of cultured neurons ( Bareyre et al., 2011 ).
How does STAT3 activation facilitate axon regeneration? Transcription
is necessary for neuronal transformation into a regenerative-capable state
after injury. In fact, multiple regeneration-associated transcriptional factors
have been identified (e.g., KLF, AP1, CREB, NFAT, and ATF3)
( Blackmore et al., 2012; Moore & Goldberg, 2011; Tedeschi, 2011 ).
STAT3, as a transcriptional activator, is known to activate more than 100
downstream targets, some of which are known to affect axon growth
including the cell cycle inhibitor P21/Cip1/Waf1 ( Tanaka et al., 2002 ),
the small proline rich protein 1a (SPRR1A) ( Pradervand et al., 2004 ), and
the IFN regulatory factor 1 (IRF1) ( Harroch, Revel, & Chebath, 1994;
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