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that transcriptional changes occur, accompanied by an upregulation of
growth-associated proteins such as GAP-43, CAP-23, and SPRRP1a in
the DRG following sciatic axotomy (
Bonilla, Tanabe, & Strittmatter,
2002; Mason, Lieberman, Grenningloh, & Anderson, 2002
).
A number of studies have since focused on the transcriptional changes
involved in regulating axon regeneration (
Moore & Goldberg, 2011;
Patodia & Raivich, 2012
); however, a large body of work has also focused
on the second messenger signaling molecule cyclic AMP (cAMP). Adult
DRG neurons have significantly lower cAMP levels compared with their
embryonic or neonatal counterparts, and this is highly upregulated as a result
of a conditioning lesion (
Qiu et al., 2002
). Further, experiments which in-
crease cAMP levels within the DRG have demonstrated enhanced dorsal
column regrowth similar to that observed following a conditioning lesion
(
Neumann, Bradke, Tessier-Lavigne, & Basbaum, 2002; Qiu et al.,
2002
). Increased levels of cAMP not only promote DRG outgrowth but also
neurite outgrowth of cerebellar, cortical, and hippocampal neurons, includ-
ing in the presence of myelin inhibitors such as MAG (myelin-associated
glycoprotein) (
Cai et al., 2001; Cai, Shen, De Bellard, Tang, & Filbin,
1999
; reviewed by
Hannila & Filbin, 2008
). cAMP-mediated neurite out-
growth has been shown to signal via three distinct pathways. One of the
pathways is transcription dependent, signaling via PKA and MEK/ERK,
triggering the phosphorylation-dependent activation of the transcription
factor CREB (cAMP response element binding protein) (
Gao et al., 2004
).
Direct expression of constitutively active CREB expressed via adenovirus
in DRGs has been shown to enhance dorsal column axon growth into
the lesion site (
Gao et al., 2004
). CREB-mediated transcription has also been
shown to increase levels of arginase-1, an enzyme involved in synthesizing
polyamines, such as arginine (
Filbin, 2003
). Further work by Filbin and col-
leagues has demonstrated that arginase-1 undergoes developmental decline
but upon reexpression or alternatively, polyamine addition, MAG-induced
neurite outgrowth inhibition can be reversed (
Filbin, 2003
). A second
pathway of cAMP-induced neurite growth is transcription independent,
again signaling through PKA, with downstream inhibition of Rho, a
Rho GTPase known to be involved in growth cone collapse (
Filbin,
2003; Hall & Lalli, 2010
). A third more recently described pathway of
cAMP-induced neurite outgrowth has been shown to involve the signaling
protein Epac (exchange protein activated by cAMP), a GEF (guanine ex-
change factor) for the Ras GTPase superfamily members, Rap1 and 2. Epac
is activated by cAMP, independently of PKA, leading to activation of Rap1
