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could produce greater regeneration than any one alone. In the case of Ocm,
whereas its downstream effects appear to involve multiple signaling path-
ways, it was not known whether Ocm fully activates these pathways or
whether one or more of them remains partially suppressed. If the latter were
true, then enhancing the activation of these pathways could have additive or
even synergistic effects. To investigate these questions, we combined intra-
ocular inflammation with elevation of cAMP and deletion of the pten gene
and found that this combination led to far greater regeneration than any of
these treatments alone ( Fig. 6.2 ). After 6 weeks, some RGCs exposed to
combinatorial treatment regenerated injured axons the full length of the op-
tic nerve and across the optic chiasm, and by 10 weeks, many axons grew in
the optic tract and beyond ( de Lima et al., 2012; Kurimoto et al., 2010 ;
Fig. 6.3 ). Some regenerating axons were seen to be myelinated ( Fig. 6.3 ),
allowing for the possibility of efficient signal conduction, an issue that
needs to be explored further.
Another major question has been whether regenerating axons are able to
navigate to their correct target areas or whether the necessary guidance signals
disappear in the adult brain. Surprisingly, RGCs subjected to combinatorial
treatment for 10 weeks showed a high degree of targeting specificity. Reg-
enerating axons navigated to areas involved in image analysis, that is, the dorsal
A
ONC alone
B
ONC+Zym
D
ONC+PTEN del
C
ONC+Zym+cAMP
E
ONC+PTEN del+Zymo+cAMP
Figure 6.2 Optic nerve regeneration induced by combinatorial treatment in mice. GAP-
43 staining 2 weeks after nerve injury in mature mice. (A) Negative control shows no
regeneration after nerve crush and no further treatment. (B) Zymosan (Zym) induces
a moderate amount of regeneration. (C) Addition of a cAMP analog, CPT-cAMP, aug-
ments the effects of Zymosan. (D) Regeneration after pten deletion. (E) The combination
of Zymosan, cAMP elevation, and pten deletion induces much greater regeneration than
any of these alone. Scale bar: 200
m
m.
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