Biology Reference
In-Depth Information
How does the simultaneous targeting of PTEN with these factors syn-
ergistically enhance axon regeneration? Elucidation of molecular mecha-
nisms underlying the synergistic effects may reveal important insights into
the process of axon regeneration. Targeting multiple factors concomitantly
could either activate complementary pathways or activate key-pathways to a
greater extent than when targeting them individually. For instance, either
inflammation/cAMP elevation or PTEN deletion results in enhanced acti-
vation of MAPK, (i.e., one of the signaling pathways known to facilitate
axon regeneration), but combined treatment leads to even greater MAPK
activation compared to single treatments (
Kurimoto et al., 2010
). In a series
of knockout mouse studies, it was demonstrated that axon regeneration in-
duced after PTEN deletion is mediated primarily by mTOR activation
(
Park et al., 2008
), whereas that induced after SOCS3 deletion is indepen-
dent of mTOR, but instead requires STAT3 activation (
Smith et al., 2009;
Sun et al., 2011
). Robust axon regeneration induced after codeletion of
PTEN and SOCS3 was concomitant with coactivation of mTOR and
STAT3 (
Sun et al., 2011
). Thus, these studies suggest that mTOR and
STAT3 represent two distinctive but complementary arms of the
regenerative program. Considering that mTOR regulates protein
translation, while STAT3 is a transcription factor involved in altering
gene expression, it is conceivable that the synergy induced after
coactivation of these pathways reflects an increase in both gene
transcription and protein translation. Furthermore, past studies using non-
neuronal cells support a positive correlation between mTOR and STAT3
activation. mTOR activation correlates with increased STAT3
expression, phosphorylation, and nuclear localization (
Goncharova et al.,
2009; Yokogami et al., 2000; Zhou et al., 2007
). When activated by
receptor tyrosine kinases, STAT3 has a relatively short half-life in the
nucleus in the presence of nuclear phosphotyrosyl phosphatase, the
nuclear export system, and SOCS family members (
Alexander & Hilton,
2004; Bhattacharya & Schindler, 2003; Mustelin, Vang, & Bottini, 2005;
Schindler, Levy, & Decker, 2007
). Through direct phosphorylation,
mTOR may positively regulate transcriptional activity of STAT3 in
RGCs. Transcriptional profiling of RGCs after injury reveals distinct
gene expression patterns among the PTEN, SOCS3, and PTEN/
SOCS3-deleted neurons. PTEN/SOCS3 double deletion results in
enhanced upregulation of a subset of regeneration-associated genes that
were shown to be moderately changed after any single deletion.
Moreover, PTEN/SOCS3 deletion upregulates mTOR's positive
