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retrogradely transported to neuron cell bodies in vivo.
At least some of the neurotrophin and receptor are ret-
rogradely transported together, perhaps in the bound
state (Hendry et al., 1974; Johnson et al., 1978; Bhat-
tacharyya et al., 1997; Ehlers et al., 1995; Tsui-Pierchala
and Ginty, 1999; Watson et al., 1999).
A sustained role for NGF within the neuron remains
controversial. To test whether retrograde transport of
NGF is necessary for survival, rat sympathetic neurons
were grown in the presence of NGF that was cova-
lently linked to 1 mm beads to prevent internalization
(Figure 7.17). Once again, only the neuronal processes
had access to the NGF. The bead-linked NGF was
almost as effective as free NGF: 81% of the neurons
survived. This experiment emphasizes the importance
of local signaling at the distal axon membrane, but it
does not exclude an important role for internalized
NGF towards achieving cell survival. For example,
preventing NGF internalization leads to a clear loss of
phosphorylated transcription factor back in the cell
body. To test whether retrogradely transported NGF
influences survival, a function blocking antibody was
introduced in the somata of sympathetic neurons
(Figure 7.17). In this case, only 60% of the neurons
survive. There is clearly some discrepancy between the
outcome of preventing internalization with beads and
blocking somatic NGF with antibody. At present, the
most parsimonious explanation is that NGF partici-
pates in both distal and somatic signaling, but the rel-
ative impact of this signal may vary with the culture
or in vivo conditions (MacInnis and Campenot, 2002;
Riccio et al., 1997; Ye et al., 2003).
While the interaction of each neurotrophin with its
receptor at the cell membrane is critical for neuron sur-
vival, it is still not clear how the survival signal is con-
veyed to the cell body. Exposure of the growing tips of
axons to NGF is sufficient to prevent cell death. This
was demonstrated in an elegant tissue culture study
where sympathetic neuron cell bodies were placed in
a central chamber that was physically isolated from the
growth media that bathed the neuritic processes
(Figure 7.16). When NGF is provided only to neurites
that grow out and reach one of the isolated side cham-
bers, 95% of the neurons survive; few survive without
NGF (Campenot, 1977, 1982). This result suggests that
the signal for survival is somehow relayed back to the
cell body.
Retrograde transport of some signal is clearly
important to neuron survival. Sympathetic neurons
die when vinblastine is used to disrupt their retro-
grade transport, and the cells can be saved with NGF
treatment (Johnson, 1978). The original concept was
that NGF, itself, carried the signal to the cell body. Both
NGF and activated TrkA receptor are internalized, and
30 hours
30 hours
A second neurotrophin receptor was originally
described as a low-affinity binding site for NGF. Now
known as p75 NTR (75 kD neurotrophin receptor), this gly-
coprotein is a member of the tumor necrosis factor
(TNFR) family of receptors (Johnson et al., 1986; Lock-
sley et al., 2001). It binds to each of the neurotrophins, as
well as to other proteins, at nanomolar levels. For
example, the beta amyloid peptide also binds to the
p75 NTR , and this may contribute to degeneration of
cholinergic brainstem neurons in Alzheimer's disease
(Yaar et al., 1997). It now appears that the uncleaved pro-
form of NGF is biologically active. The proforms of NGF
and BDNF are released and cleaved in the extracellular
space, and proNGF is a high-affinity ligand for the
p75 NTR receptor (Lee et al., 2001).
The p75 NTR receptor does not have a uniform role in
naturally occurring cell death. It can both improve and
22% survival
95% survival
FIGURE 7.16 The NGF signal can be transduced at the tips of
growing neuronal processes. Sympathetic neurons were placed in a
special tissue culture system that permitted the cell bodies and neu-
rites to be bathed in different media. (Left) Most neurons died when
grown in the absence of NGF for 30 hours. (Right) Neurons could
be kept alive by adding NGF only to the compartments with
growing neurites. In both cases, an antibody against NGF was added
to the central compartment to prevent activation of TrkA. (Adapted
from Campenot, 1977, 1982; MacInnis and Campenot, 2002)
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