Biology Reference
In-Depth Information
the molecular mechanism of signaling to Rho is partly understood. The
p75NTR coreceptor can physically interact with NgR1 to mediate
intracellular signaling (
Wang, Kim, Sivasankaran, Segal, & He, 2002;
Wong et al., 2002; Yamashita, Higuchi, & Tohyama, 2002
). In many
neurons, TROY substitutes for p75NTR, and other proteins such as
Lingo-1 participate as components of the NgR1 complex (
Mi et al.,
2004; Park et al., 2005; Shao et al., 2005
). Both p75NTR and TROY
signal to activate Rho (
Park et al., 2005; Shao et al., 2005; Yamashita &
Tohyama, 2003
). PirB is expressed in a subset of neurons in the brain,
and interfering with PirB activity, either genetically or with a function-
blocking antibody, reduces neurite outgrowth inhibition in response to
the Nogo-66, MAG, OMgp, and myelin
in vitro
. Molecular antagonists
of myelin-derived inhibitors and their receptors have shown some
promise in promoting repair following spinal cord injury (SCI), while the
results from gene knockout studies have been shown variable results
(reviewed in
McDonald, Bandtlow, & Reindl, 2011
).
Extracellular matrix deposited at a glial scar that forms after injury in
the CNS is highly enriched in chondroitin sulfate proteoglycans (CSPGs),
which are potent inhibitors of axon growth (
Fitch & Silver, 2008; Rudge
& Silver, 1990
). The glial reaction to CNS injury occurs almost
immediately after injury as a mechanism to protect healthy CNS tissue
from inflammatory damage and to repair the blood-brain barrier (
Fitch
& Silver, 2008
). Astrocytes undergo reactive gliosis and are a major
contributor
to the inhibitory nature of
the glial
scar by releasing
CSPGs. Protein tyrosine phosphatase
) and leukocyte
common antigen-related phosphatase have been identified as CSPG
receptors, and antagonism of these receptors pharmacologically or
through gene disruption promotes axon regeneration (
Fisher et al.,
2011; Fry, Chagnon, L´pez-Vales, Tremblay, & David, 2009; Shen
et al., 2009
). Recently, NgR1 and NgR3 have also been shown to
contribute to CSPG-mediated inhibition (
Dickendesher et al., 2012
).
Many groups have established that inactivating Rho is sufficient to
overcome growth inhibition on CSPG substrates (
Borisoff et al., 2003;
Dergham et al., 2002; Lingor et al., 2007; Monnier, Sierra, Schwab,
Henke-Fahle, & Mueller, 2003
), but
s
(PTP
s
the full
signaling cascades
still
need to be elaborated.
Chemorepulsive axon guidance molecules are other inhibitors that guide
axon growth during development of the nervous system, and many are
expressed in the adult CNS or may be upregulated after CNS injury. Like
