Biology Reference
In-Depth Information
5. EXOGENOUS NEUROTROPHIC FACTORS AND RGC
AXONAL REGENERATION
Neurotrophic factors influence RGC viability and regenerative
potential signal via different receptor complexes and signaling cascades,
although there is some convergence of these intracellular pathways. These
pathways have been reviewed in detail many times, but a brief summary is
pertinent here because these cascades relate to other mechanistic studies al-
luded to in previous paragraphs.
BDNF andNT-4/5 activation ofMAPK-ERK and PI3K-AKTpathways
results in process outgrowth, cellular differentiation, and cell survival during
development and neuronal support in the mature CNS. Activation of the
PLC
g
1 pathway results in increased mobilization of calcium stores and
influences synaptic plasticity by activation of calcium-dependent kinases
(
Kaplan & Miller, 2000
). These neurotrophins also bind to the low-affinity
neurotrophin receptor p75, which can result in negative effects on cell survival
via proapoptotic signaling and growth cone collapse. There are complex inter-
actions between these receptors and the high-affinity Trks. BDNF binding to
TrkB and p75 also activates other membrane proteins that themselves have the
potential to activate specific signaling pathways. For example, BDNF binding
to TrkB activates ankyrin repeat-rich membrane spanning (
Kong, Boulter,
Weber, Lai, & Chao, 2001
), a scaffold protein that regulates synaptic plasticity
and dendritic stability and branching viamodulation of microtubule-associated
proteins (
Higuero et al., 2010
). p75 interaction with ephrin-As alters axon
guidance and branching (
Marler, Poopalasundaram, Broom, Wentzel, &
Drescher, 2010; Poopalasundaram, Marler, & Drescher, 2011
).
CNTF acts through a tripartite receptor complex. The binding of CNTF
to the CNTFa subunit recruits two other components, LIF-R
b
and gp130,
which then initiates the signaling process by activating the JAK/STAT, Ras/
MAPK, and PI-3K/Akt pathways. Importantly, the strength and duration of
cytokine signaling via JAK/STAT are tightly regulated by SOCS proteins;
thus, expression of SOCS3 in RGCs reduces any impact of retinally derived
cytokines such as CNTF and LIF on RGC survival and axonal regeneration
after injury (
Hellstr¨m, Muhling, et al., 2011; Smith et al., 2009
), and
overexpression of SOCS3 in RGCs all but blocks their ability to
regenerate an axon (
Hellstr¨m, Muhling, et al., 2011
). Deletion of SOCS3
in the retina prior to ON crush significantly improves regeneration,
correlated with inhibition of mTOR pathway activity (
Smith et al., 2009
).
