Further studies are required to define the full compliment of caspases that
are present in various neurons at different times during development and
to identify which of these are activated during the process of neurotrophin
withdrawal-induced PCD. In addition, current evidence suggests at least
two possible routes of caspase activation in other cell types (Figure 6.1); and
further studies are required to determine which of these contribute to caspase
activation after neurotrophin withdrawal. On the one hand, the requirement
for macromolecular synthesis raises the possibility that neurotrophin withdrawal
is accompanied by synthesis of one of the death receptors and/or
the corresponding ligand. On the other hand, the observation that reactive
oxygen species are produced during neurotrophin withdrawal-induced
PCD179 raises the possibility that release of cytochrome c to the cytosol is
involved in caspase activation in this setting. Although the effects of Bcl-2
on cytochrome c release and neurotrophin withdrawal-induced apoptosis
(see Section 6.2) are consistent with this possibility, it remains to be determined
how (or even whether) cytochrome c release is induced after neurotrophin
withdrawal.