Biology Reference
In-Depth Information
peripheral nerve graft (
Hellstrom et al., 2011
). Together, these data support a
model in which SOCS3 suppresses axon regeneration by antagonizing the
cytokine regulated gp130 signaling pathway, and that relieving SOCS3
activity further potentiates cytokine (e.g., CNTF) effects on regeneration.
The gp130 pathway may be triggered by inflammatory cytokines after
injury but would remain unproductive owing to subsequent induction of
and suppression by the SOCS proteins.
What are the downstream intracellular mechanisms underlying the en-
hanced axon regeneration induced by CNTF elevation or SOCS3 deletion?
STAT3 is activated in RGCs after CNTF treatment, and JAK/STAT inhib-
itors attenuate CNTF-stimulated neurite outgrowth from purified RGCs
(
Leibinger et al., 2009; Lingor et al., 2008; Muller et al., 2009
). These
data indicate that CNTF exerts its effect at least in part through the JAK/
STAT pathway. CNTF has also been shown to activate several other
intracellular signaling pathways including MAPK/ERK and PI3K/AKT
pathways (
Alonzi et al., 2001; Leibinger et al., 2009; Muller et al., 2009;
Park et al., 2004
). Inhibition of MAPK and PI3K reduces CNTF's effect
on axon growth in peripheral neurons and RGCs (
Alonzi et al., 2001;
Dolcet et al., 2001; Muller et al., 2009; Park et al., 2004
), suggesting that
CNTF may activate multiple pathways to induce axon regeneration.
Clear evidence indicating STAT3 as the primary effector of axon
regeneration induced by SOCS3 deletion came from a study using
double knockout mice lacking SOCS3/STAT3 in adult neurons. While
single SOCS3 knockout mice permit significant axon regeneration in the
optic nerve, mice bearing double SOCS3/STAT3 deletion fail to
regenerate axons (
Sun et al., 2011
), indicating that STAT3 is required for
the axon regeneration in the background of SOCS3 deletion. What
downstream targets could mediate STAT3's effects on axon regeneration?
Gene profiling studies using purified RGCs demonstrate that many genes
implicated in PNS axon regeneration, such as Jun, GAP43, Id2, SOX11,
ATF3, and galanin, are significantly altered in axon-regenerating RGCs
after SOCS3 deletion (
Sun et al., 2011
), consistent with the notion that
the JAK/STAT pathway is a critical one for PNS axon regeneration.
3.3. STAT3: A facilitator of axon regeneration
The JAK/STAT system provides direct mechanisms to respond to extracel-
lular stimuli. Many ligands including cytokines, hormones, and growth fac-
tors, and their receptors activate the JAK/STAT pathway; once activated,
