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et al., 1998
). We next reasoned that if Rho regulates growth cone collapse,
perhaps blocking Rho activity would be sufficient to stimulate axon growth.
This was first demonstrated by placing neural cells on inhibitory substrates in
culture and showing that inactivation of Rho with C3 transferase promoted
neurite growth on growth inhibitory substrates (
Lehmann et al., 1999
).
Growth cone collapse is a result of the disassembly of the actin and
microtubule cytoskeleton. The molecular mechanisms responsible for
Rho activation leading to cytoskeletal disassembly are still beginning to
be elucidated. The actin cytoskeleton is regulated by accessory proteins that
include cofilin, a protein that regulates depolymerization and severing of
actin filaments. In the presence of CNS inhibitors, Rho and its downstream
effector Rho kinase (ROCK) are both activated (
Alabed, Grados-Munro,
Ferraro, Hsieh, & Fournier, 2006; Dergham et al., 2002
) and in turn
activate LIM kinase, which regulates cofilin (
Hsieh, Ferraro, & Fournier,
2006
). CNS inhibitors also signal through Rho to affect elements of the
microtubule cytoskeleton. Inhibitors enhance the interaction between
RhoA and the cytosolic phospho-protein collapsin-response mediator
protein 4 (CRMP4). CRMP4 is an actin and microtubule-binding
protein that is a key mediator of growth cone collapse in response to
CNS inhibitors (
Alabed, Pool, Tone, & Fournier, 2007; Alabed, Pool,
Tone, Sutherland, & Fournier, 2010
). Antagonism of ROCK, LIM kinase,
or CRMP4 effectively promotes neurite outgrowth on growth inhibitory
substrates (
Alabed et al., 2007; Fournier, Takizawa, & Strittmatter, 2003;
Hsieh et al., 2006
)(
Fig. 6.1
).
1.2. Growth inhibition in the CNS
The inhibitors of CNS regeneration can be classified into three main cate-
gories: (1) myelin-associated inhibitors, (2) inhibitors associated with the
glial scar that forms after injury, and (3) Inhibitors that function as guidance
cues during development. There are many types of ligands and receptor
complexes associated with signaling by the many axon growth inhibitors.
However, most, if not all, inhibitory signaling complexes from the three
classes of growth inhibitory molecules converge to the Rho pathway.
The major myelin-derived inhibitors of axon regeneration are MAG,
Nogo, and OMgp (
Cafferty, Duffy, Huebner, & Strittmatter, 2010;
Filbin, 1996; Kottis et al., 2002; McKerracher et al., 1994; Schwab, 2010;
Wang, Koprivica, et al., 2002
). Early experiments showed that
inactivation of Rho or ROCK was sufficient to promote neurite growth
on myelin substrates (
Lehmann et al., 1999
). All three growth inhibitory
