Biology Reference
In-Depth Information
as well as other factors such as ciliary neurotrophic factor (CNTF), leukemia
inhibitory factor (LIF), glial cell-derived neurotrophic factor (GDNF),
insulin-like growth factor-1 (IGF-1), the fibroblast growth factors (FGFs),
and hepatocyte growth factor (HGF). It is, of course, axiomatic that the
regrowth of injured axons requires viable parent neurons; thus, the impact
of these factors on RGC survival also needs to be considered. In this context,
studies aimed at developing therapies to enhance RGC responsiveness after
ON trauma have direct ophthalmological relevance becauseRGC loss is seen
in clinical conditions such as glaucoma, retinal ischemia, retinitis pigmentosa,
diabetic retinopathy, optic neuritis,multiple sclerosis, andAlzheimer's disease
(e.g.,
Harvey et al., 2006; Johnson et al., 2011; Kern & Barber, 2008
for
reviews). Many studies have examined the impact of neurotrophic factors
on RGC survival in animal models of these ophthalmic conditions, but
while acknowledging their seminal importance, here we focus on how
these various factors influence the RGC regenerative process
per se
.We
also briefly comment on signaling pathways recruited by these factors and
how they (i) overcome the loss of intrinsic regenerative capacity in adult
RGCs and (ii) interact with signals from the extracellular environment to
ameliorate growth-inhibitory components of the injured mature CNS.
2. TROPHIC DEPENDENCE OF RGCs DURING
DEVELOPMENT
The commonly held view is that RGCs compete for neurotrophic
support; those that in some way fail to obtain sufficient support die, resulting
in activation of proapoptotic pathways and the loss of over half the RGC
population during the developmental period. Thus, early postnatal removal
of a central target such as the SC during the period of naturally occurring cell
death causes a rapid and massive increase in RGC death, while addition of
factors such as BDNF or NT-4/5 results in increased RGC survival (
Caleo,
Menna, Chierzi, Cenni, & Maffei, 2000; Cui & Harvey, 1994, 1995; Ma,
Hsieh, Forbes, Johnson, & Frost, 1998; Rodriguez-Tebar, Jeffrey,
Thoenen, & Barde, 1989; Spalding, Cui, & Harvey, 1998; Vanselow,
Dutting, & Thanos, 1990
). Consistent with the concept of target-derived
support, BDNF is synthesized by cells in the SC and is retrogradely
transported back to RGCs (
Frost, 2001; Ma et al., 1998; Marotte,
Vidovic, Wheeler, & Jhaveri, 2004; Pease, McKinnon, Quigley,
Kerrigan-Baumrind, & Zack, 2000
).
