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s
(PTP-
)(
Shen et al., 2009
), transmembrane leukocyte common antigen-
related phosphatase (
Fisher et al., 2011
), and particular isotypes of NgR
(
Dickendesher et al., 2012
). Despite this plethora of receptors, many
inhibitory molecules utilize a final common signal transduction pathway to
arrest axon growth that involves activation of the small GTPase RhoA
(
Niederost, Oertle, Fritsche, McKinney, & Bandtlow, 2002; Yamashita &
Tohyama, 2003
). In general, studies that counteract only one or multiple
ligands and/or receptor have not produced extensive axon regeneration in
the optic nerve, and even counteracting multiple receptors or blocking
the activity of RhoA yields only modest levels of regeneration
(
Dickendesher et al., 2012; Fischer, He, & Benowitz, 2004; Fischer,
Petkova, et al., 2004
). Elsewhere in the CNS, deletion of Nogo or
Omgp can induce sprouting of the corticospinal tract and serotonergic
axons, though not long-distance regeneration, while deletion of MAG
impairs sprouting. In addition, a triple knockout of all three genes has no
greater effect on the levels of sprouting than deletion of any one of these
molecules alone (
Lee, Geoffroy, et al., 2010
). Also, deletion of NgR and
semaphorin receptors do not promote long-distance axon regeneration
(
Lee, Chow, et al., 2010
). However, when strategies that counteract cell-
extrinsic inhibitors of growth are combined with methods that activate
RGCs' intrinsic growth state, the effects are far greater than either strategy
alone. Thus, expressing a dominant-negative form of NgR in RGCs has
little effect in promoting axon regeneration through the optic nerve, but
triples the level of regeneration when RGCs' intrinsic growth state is
activated (
Fischer,He,etal.,2004
). Blocking the activity of RhoA has a
moderate effect on regeneration (
Lehmann et al., 1999
), but when
combined with intraocular inflammation, RhoA inhibition enables almost
all axons that are seen proximal to the injury site to pass through this
site, a region at which most axon growth normally stops (
Fig. 6.1
Gand
H;
Fischer, Petkova, et al., 2004
). Likewise, combining intraocular
inflammation with genetic deletion of the genes that encode PTP-
plus
all three isoforms of NgR leads to considerably more regeneration than
any of these manipulations alone (
Dickendesher et al., 2012
).
s
5. SYNERGY BETWEEN INTRAOCULAR INFLAMMATION
AND DELETING SUPPRESSORS OF CELL SIGNALING
The discovery that several methods can activate RGCs' intrinsic
growth state raises the question of whether these approaches act through
a common final pathway or whether they act in complementary ways that