Biology Reference
In-Depth Information
The precise trophic dependence of RGCs has best been revealed by
studies of highly purified RGCs in culture where RGC responsiveness
can be studied in the absence of other cell types. Survival of embryonic
(E18) and postnatal (P1, P8) RGCs in culture is strongly potentiated by a
combination of BDNF and cAMP/depolarization. However, embryonic
and mature cells have particular preferences: the survival of embryonic
RGCs is best potentiated by target (tectum)-derived signals that have yet
to be fully characterized (
Meyer-Franke, Kaplan, Pfieger, & Barres, 1995
)
and BDNF is the only trophic factor that potentiates the effect of cAMP,
although it has little effect on its own. As they mature, RGCs acquire
sensitivity
to
additional
trophic
factors which
in
combination
þ
þ
(BDNF
insulin) can increase survival to 90% even in the absence
of cAMP potentiation (
Meyer-Franke et al., 1995
).
Members of the neurotrophin family mediate many of their effects via a
group of receptor tyrosine kinases (Trks), binding with high affinity. BDNF
and NT4/5 signal through TrkB and this receptor is expressed by RGCs
during development. There is already decreased expression by P10, at about
the time RGC axonal innervation and initial synaptogenesis in the SC are
complete (
Rickman & Brecha, 1995; Ugolini, Cremisi, & Maffei, 1995
).
The receptors themselves play a key role in the response to neurotrophins
as their expression and translocation to the plasma membrane are tightly
regulated. TrkB receptors are internalized following BDNF binding
(
Sommerfeld, Schweigreiter, Barde, & Hoppe, 2000
), resulting in less
available TrkB on the membrane, and TrkB mRNA is downregulated
resulting in long-term loss of sensitivity (
Chen & Weber, 2004
). However,
TrkB expression on the cell surface can be increased by increasing cAMP
levels by neuronal activity or forskolin, explaining the role of cAMP in
potentiating survival in RGCs in culture (
Meyer-Franke et al., 1995
).
Nonetheless, studies involving the removal of BDNF, NT-4/5, or
relevant receptors, such as trkB, using genetic ablation or antibody
blocking methods, suggest that TrkB signaling regulates the timing of cell
death but does not alter the total number of surviving RGCs after the early
period of developmental cell death (
Pollock et al., 2003; Rohrer, LaVail,
Jones, & Reichardt, 2001
).
Importantly, it is now clear that the switch to target-derived neuro-
trophin sensitivity in developing RGCs is an active process and correlates
with their birth date and the time taken for RGC axons to reach and
then grow into central target sites in the brain (
Dallimore, Cui, Beazley,
CNTF
