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system, and its overexpression in the retina leads to the
complete loss of cells (White et al., 1996).
As suggested by its homology to the reaper gene
product, p75 NTR activation has been shown to promote
apoptosis in several developing neuronal populations.
In p75 NTR knockout mice there is less cell death in the
retina, the cholinergic brainstem, and the spinal cord
mantle zone (Frade and Barde, 1999; Naumann et al.,
2002). The death-promoting activity of the p75 NTR may
be evoked by its high-affinity ligand, the uncleaved
neurotrophin. When SCG neurons are grown in the
presence of mature NGF, there is virtually no cell
death, but the neurons display a significant increase
in TUNEL labeling when grown in the presence of
pro-NGF (Figure 7.18).
Most experiments have examined the effect of NGF
only (because it was not yet known that pro-NGF was a
good ligand). In these experiments, the relative amount
of TrkA and p75 NTR activity determines whether life or
death occurs. Rat brain oligodendrocytes grown in
culture express the p75 NTR receptor, but not TrkA, and
NGF treatment kills the majority of cells (Casaccia Bon-
nefil et al., 1996). In the developing retina, the depletion
of endogenous NGF with antibody results in better sur-
vival of retinal neurons. The ability of NGF to kill retinal
neurons is apparently mediated by p75 NTR because anti-
bodies against this receptor prevents the cell death
(Frade et al., 1996). In cultured sympathetic neurons that
express both TrkA and p75 NTR , BDNF is able to kill these
cells because it selectively activates the p75 NTR receptor
and not TrkA (Bamji et al., 1998). Thus, the relative
amount of each ligand (proneurotrophin and neu-
rotrophin), and each receptor (Trks and p75 NTR ) makes it
tricky to predict the outcome for any neuron population.
Additional members of the TNFR family contribute
to neuronal cell death during development. In the
cortex, some neuroblasts express the TNFR family
member called Fas, and neighboring cells express its
ligand, FasL. Activation of this receptor produces cell
death in the primary cultures of cortex neuroblasts.
Spinal motor neurons also express Fas and its ligand
during the embryonic period of normal cell death.
Primary cultures of motor neurons can be kept alive
when grown in the presence of a compound that blocks
Fas activation (Cheema et al., 1999; Raoul et al., 1999).
Members of the TNFR family initiate the cell death
process by recruiting a broad range of intracellular
messengers (Figure 7.18). The Fas receptor binds to an
adapter protein (FADD) that leads to the activation of
caspase-8, an enzyme that is directly involved in pro-
moting cell death (see Caspases: Agents of Death). The
survival-promoting influence of p75 NTR may employ a
transcription activator called nuclear factor kB (NF-kB)
which is recruited to enter the nucleus (Fig 7.18).
-NGF
anti-NGF
-NGF
Pep-1/anti-NGF
complex
NGF
30 hours
24 hours
81% survival
60% survival
Ab
NGF
FIGURE 7.17 Experiments were designed to test whether inter-
nalized NGF contributes to sympathetic neuron survival. (Left) NGF
is covalently bound to beads, preventing internalization but per-
mitting local activation of the TrkA receptor. In this case, 81% of the
neurons survive for 30 hours. (Right) Sympathetic neuron cell bodies
are exposed to a protein delivery system (Pep-1-anti-NGF complex)
that permits delivery of anti-NGF antibody to enter the cells. With
NGF neutralized within the soma, 40% of the sympathetic neurons
died. (Adapted from MacInnis and Campenot, 2002; Ye et al., 2003)
worsen the chance for neuron survival. There is evi-
dence that p75 NTR collaborates with Trk receptors to
enhance ligand binding and phosphorylation (Chao,
1994). Cutaneous sensory trigeminal neurons cultured
from p75 NTR knockout mice require a fourfold greater
concentration of NGF in order to survive (Davies et al.,
1993). Consistent with this survival-promoting role,
the complete loss of p75 NTR function in mice leads to a
50% reduction in lumbar DRG neuron number (von
Schack et al., 2001).
Unlike Trk receptors, the p75 NTR does not have an
intracellular catalytic domain (Figure 7.13), but it does
activate several intracellular signaling pathways. One
intriguing clue about the function of p75 NTR comes
from its homology to other members of the TNF recep-
tor family. Each of these proteins has a “death domain”
on the cytoplasmic tail which is similar to the reaper
gene product in Drosophila . The deletion of reaper
blocks most cell death in the embryonic fly nervous
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