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et al., 2008
). Lingo-1 may also play an important role in regulating the
activation state of Rho and regulating the localization of Rho-GDI
(
Zhang et al., 2009
). Neurons that overexpress Rho-GDI are unable to
respond to growth inhibitory proteins, a finding that supports the critical
role of Rho-GDI in mediating the interaction between p75NTR and
Rho (
Yamashita & Tohyama, 2003
). Rho-GDI is also important to the
mechanism of C3 transferases to inactivate Rho. After activation of Rho
at the membrane, GDI extracts Rho and forms an inactive Rho-GDI com-
plex in the cytosol. C3 transferases add an ADP-ribose to the free form of
Rho, which then leads to GDI binding and accumulation of Rho-GDI
complexes in the cytoplasm (
Vogelsgesang, Pautsch, &Aktories, 2007
). This
reaction takes Rho out of the activation pathway.
2. AXON REGENERATION AND FUNCTIONAL RECOVERY
IN PRECLINICAL STUDIES
2.1. Long-distance axon regeneration
Independent verification of axon regeneration
in vivo
in different models and
with different methods is important because results of studies of axon regen-
eration
in vivo
are subject to technical variability (
Steward, Popovich,
Dietrich, & Kleitman, 2012; Steward, Zheng, & Tessier-Lavigne, 2003
).
Long-distance axon regeneration promoted by inactivation of either
ROCK or Rho is robust, has been documented in optic nerve injury in
rats, and has been shown in various models of SCI in rats and mice,
including injury of the corticospinal tract. Moreover, different methods
from anterograde tracing to studying changes in gene expression have
been used to verify long-distance axon regeneration. First, in tissue
culture, there is a wealth of evidence documenting the importance of
Rho as the key intracellular signaling switch that regulates axon growth
on growth inhibitory substrates and allows axons to cross from permissive
substrates across an inhibitory boundary (
Lehmann et al., 1999; Monnier
et al., 2003; Shearer et al., 2003
). Second, inactivation of Rho to
promote axon regeneration
in vivo
has been demonstrated in several
model systems.
The optic nerve is a well-established model system of axon regeneration
in the CNS. RGCs send long projection axons into the optic nerve with no
collateral branches. The optic nerve is pure white matter, a very inhospitable
environment for regeneration. Axons abruptly stop at a microcrush lesion,
making assessment of regeneration very straightforward (
Selles-Navarro,
Ellezam, Fajardo, Latour, &McKerracher, 2001
). Cell-permeable C3 added
