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which induces downstream signaling through AKT and B-Raf (and subse-
quently MEK and ERK1/2), with inhibitory activity against Rho (reviewed
by
Peace & Shewan, 2011
); inactivation of RhoA, in turn, promotes CNS
axon regeneration (see Volume 105, Chapter 6). Expression of Epac in
DRG neurons enhances neurite outgrowth and is reportedly as effective
as cAMP elevation in promoting regeneration on spinal cord tissue, with
these effects being abolished following Epac knockdown (
Murray &
Shewan, 2008
). The same study also found that asymmetric activation of
Epac promotes attractive growth cone turning in a similar fashion to cAMP.
This may be of particular interest regarding integrin-dependent outgrowth
as the cAMP-Epac-Rap1 pathway is known to be involved in regulating
integrin-dependent adhesion in nonneuronal cells (
Enserink et al., 2004;
Rangarajan et al., 2003
), and integrins have been implicated in growth cone
turning (
Hines et al., 2010
).
2.2. Integrins and axon regeneration
As described above, integrins play a key role in the coordinated development
of the CNS and PNS. Axon elongation proceeds successfully due in large
part to discretely balanced integrin and ECM expression occurring in devel-
opment. In adult CNS, however, especially in response to injury, neurons
are less likely to express high levels of integrins compared to their developing
counterparts, leaving neurons without the necessary receptors to regrow
through lesioned environments often characterized by highly upregulated
ECM (
Hammarberg, Wallquist, Piehl, Risling, & Cullheim, 2000; Jones,
1996; Pinkstaff, Detterich, Lynch, & Gall, 1999
).
A developmental change in integrin expression is also evident in the PNS.
In a direct
in vitro
comparison between embryonic and adult DRG neurons
plated on inhibitory substrates, embryonic neurons were able to adapt by in-
creasing integrin expression on the surface membrane in order to successfully
grow on the inhibitory substrates (
Condic, 2001; Condic, Snow, &
Letourneau, 1999
). Additionally, neurite outgrowth is partially reduced if
b
1 integrin is blocked in embryonic neurons (
Blackmore & Letourneau,
2006
). Adult neurons donot have a similar capacity to adapt, rather exogenous
expression of the appropriate integrin receptor is necessary to overcome in-
hibition (
Andrews et al., 2009; Condic, 2001
). Endogenously within the
PNS, reexpression of integrin subunits following peripheral (conditioning)
injury is common, with several studies demonstrating an upregulation of
a
6,
a
7, and
b
1 (protein and mRNA) in DRG neurons (
Fig. 3.1
A), which
