Biology Reference
In-Depth Information
receptor
a
component (
Davis et al., 1993; Stahl & Yancopoulos, 1994
).
Besides, its neuroprotective role, several studies have reported the axon
regenerative effects of CNTF. Early evidence supporting a positive role
demonstrated that administering recombinant CNTF enhances the number
of regenerating axons after sciatic nerve transection (
Sahenk, Seharaseyon,
& Mendell, 1994
). CNTF at a high concentration was shown to enhance
neurite outgrowth from purified RGCs
in vitro
, and repeated intravitreous
delivery of recombinant CNTF enhances axon regeneration after optic
nerve injury (
Lingor et al., 2008; Muller, Hauk, Leibinger, Marienfeld, &
Fischer, 2009; Smith et al., 2009
). Further, recombinant CNTF protects
RGCs from death after axotomy and promotes axon regeneration into a
transplanted peripheral nerve graft (
Cui & Harvey, 2000; Mey & Thanos,
1993; Park, Luo, Hisheh, Harvey, & Cui, 2004
). However, the extent of
axon growth in RGCs induced after bolus injection of CNTF has been
quite modest (i.e., only small numbers of neurons extending lengthy
axons). The low efficacy could result from the relatively short half-life of
CNTF or from the inner retinal membrane acting as a physical barrier (
van
Adel, Arnold, Phipps, Doering, & Ball, 2005
). In support of this idea, viral
delivery of CNTF into the vitreous body, which allows integrated
expression and sustained supply of CNTF from the inner retinal cells,
promotes considerable axon regrowth (
Leaver et al., 2006
). In contrast,
other studies, in fact, have reported a minimum role of CNTF in
promoting axon regeneration. CNTF elevation failed to stimulate optic
nerve regeneration
in vivo
, and it failed to enhance neurite outgrowth in
retinal explants
ex vivo
(
Cen et al., 2007; Jo, Wang, & Benowitz, 1999;
Yin et al., 2003, 2006, 2009
). These data challenged the role of CNTF as
a direct stimulator of axon regrowth. A recent study provided hints on
why some injured neurons respond so poorly to CNTF. Following an
axon injury, SOCS3 is upregulated rapidly in injured neurons (
Fischer
et al., 2004; Park et al., 2009
), an event which likely restricts the actions of
CNTF on neurons.
Smith et al. (2009)
reported that conditional deletion
of SOCS3 in RGCs was sufficient to enhance axon regeneration after
optic nerve injury. This effect can be abolished with concomitant deletion
of gp130, indicating that gp130 mediates the SOCS3 knockout effect on
axon regeneration (
Smith et al., 2009
). Further, while injection of CNTF
alone yielded only limited extent of axon regeneration, CNTF treatment
in SOCS3-deleted mice led to robust axon regeneration (
Smith et al.,
2009
). More recently, viral-mediated overexpression of DN SOCS3 in
adult RGCs diminished CNTF-induced axon regeneration into a
