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in the presence of macromolecular synthesis. It will,
therefore, be important to study naturally occurring
cell death in many areas of the nervous system in order
to determine whether protein synthesis is an obligate
part of the death pathway.
INTRACELLULAR SIGNALING
Afull description of the molecular pathways that
support apoptosis can quickly overpower the reader
with a list of acronyms. In simplified form, the devel-
oping neuron contains two types of proteins in its cyto-
plasm: those that maintain survival and those that
mediate death. When a survival factor binds to its
receptor, anti-apoptotic proteins are activated by
phosphorylation. Moreover, the expression of anti-
apoptotic proteins increases. When survival factors are
withdrawn, pro-apoptotic proteins are activated by
phosphorylation, and their expression increases.
Therefore, the vital purpose of a survival factor is to
upregulate the function or expression of pro-apoptotic
proteins and suppress the anti-apoptotic proteins.
Although growth factors influence developmental
events besides cell death (e.g., mitosis, differentiation,
and axon outgrowth), many of the intracellular signals
have been identified during studies of cancer cell
growth. To make this discussion somewhat manage-
able, we will only cover the cytoplasmic signals that
are most relevant to the survival of neurons during
normal development.
Neurotrophin signal transduction, the best charac-
terized pathway in neural tissue, involves the sequen-
tial recruitment and activation of several kinase
pathways. Activation ultimately leads to modification
of existing cytoplasmic or membrane proteins, and
regulation of gene transcription. The binding of NGF
to the TrkA protein induces receptor dimerization, fol-
lowed by the rapid phosphorylation of 5 tyrosine
residues on the cytoplasmic tail by neighboring Trk
receptors (Kaplan et al., 1991b). Many components of
this intracellular pathway are identical to those that are
recruited by the sevenless receptor tyrosine kinase and
participate in fly eye differentiation (see Chapter 4).
The phosphorylation sites on the Trk receptor serve as
docking sites for the cytoplasmic molecules that will
propagate the signal toward cytoplasmic kinases and
the nucleus (Figure 7.22). Shc is one of the first adaptor
proteins that binds to the Trk receptor, and is phos-
phorylated by it. In fact, the Shc binding site appears
to be critical to the survival of NT-4-dependent sensory
neurons in vivo (Minichiello et al., 1998).
As shown in Figure 7.23, the first major kinase
pathway is activated by the recruitment of a second
adaptor protein (Grb2, growth factor receptor-bound
protein-2) and a docking protein (Gab1, Grb2-associ-
ated Binder-1). In this pathway, a phosphotidylinositol
3-kinase (PI3K) activates a serine/threonine kinase,
called Akt. The PI3K-Akt pathway provides a crucial
intracellular signal for keeping NGF-dependent
A
NGF
Cycloheximide or
actinomycin-D
-NGF
B
Control
DRG cells
Motor
neurons
Block Translation
CHX
Block Transcription
AM-D
FIGURE 7.21 Neuron cell death can be delayed by blocking
protein synthesis. A. Sympathetic neurons die within two days,
when NGF is removed from the culture media (left). When either a
translation blocker (cyclohexamide, CHX) or a transcription blocker
(actinomycin-D, AM-D) was added to NGF-deprived cultures, sym-
pathetic neurons were rescued (right). B. The synthesis of mRNA
and protein is also required for naturally occurring cell death in
vivo. In control chick embryos, pyknotic motor neurons and DRG
neurons are counted during normal development (top). When chick
embryos are treated with CHX during the time when motor neuron
and DRG cell death is at its greatest, the number of pyknotic neurons
is decreased (middle). Similarly, when chick embryos are treated
with AM-D, there is a reduction in the number of pyknotic neurons.
(Adapted from Martin et al., 1988; Oppenheim et al., 1990).
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