Biology Reference
In-Depth Information
Maffei, 1999
), and that BDNF increases RGC survival but antagonizes the
effects of intraocular inflammation on regeneration (
Pernet & Di Polo, 2006
).
One study questioned the role of Ocm in mediating the effects of intra-
ocular inflammation (
Hauk, Muller, Lee, Schwendener, & Fischer, 2008
),
but the results of that study were highly ambiguous (
Yin et al., 2009
).
The authors reported that immunodepletion of Ocm failed to diminish
regeneration, but used a commercial antibody that was not proven to be
neutralizing, and reported preadsorption controls in Western blots that
may have adsorbed out many IgGs nonspecifically.
3. STIMULATING OPTIC NERVE REGENERATION BY
ACTIVATING CELL SIGNALING PATHWAYS
Several signal transduction pathways seem to regulate axon outgrowth
in RGCs. In dissociated retinal cultures, the axon-promoting effects of Ocm
are suppressed by blocking several signaling transduction pathways at once,
but are not blocked by inhibiting the MAP kinase, PI3 kinase, or Jak/STAT
pathway alone (
Yin et al., 2006
).
In vivo
, intraocular inflammation increases
activation of MAPK and S6 kinase but not Akt in retinal laminae containing
RGC somata and dendrites (
Kurimoto et al., 2010
). S6 kinase is important in
regulating transcription and protein translation, whereas Akt is a down-
stream effector of the PI3K pathway. These data suggest that Ocm activates
the MAPK pathway, but that the PI3 kinase pathway may need to be con-
stitutively active for regeneration to occur.
Appreciable levels of regeneration can also be achieved by derepressing par-
ticular signal transduction pathways. PTEN is a lipid and protein phosphatase
that suppresses the PI3 kinase-Akt pathway, whereas SOCS3 suppresses signal-
ing through the Jak-STAT pathway. Deletion of the
pten
gene inRGCs is suf-
ficient to promote appreciable optic nerve regeneration in adult mice (
Park
et al., 2008
). Deletion of the
socs3
gene by itself results in only modest regen-
eration, but has a marked effect in the presence of exogenous CNTF (
Smith
et al., 2009
). It should be noted, however, that in the absence of
socs3
deletion,
CNTF has very little effect on regeneration (
Smith et al., 2009
), in agreement
with the results of many other studies (
Cohen, Bray, & Aguayo, 1994; Leon
et al., 2000; Lingor et al., 2008; Pernet & Di Polo, 2006; Weise et al., 2000
).
Socs3 expression increases in RGCs after optic nerve injury and increases
even further with intraocular inflammation, thus diminishing the ability of
CNTF to promote growth (
Fischer, Petkova, et al., 2004
). In the model in
