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More than three receptor proteins are expressed in
vivo because each Trk receptor gene is differentially
spliced. In fact, the trkC genes may encode for up to
eight different TrkC receptor proteins. There are a
number of truncated Trk receptors (those missing the
tyrosine kinase domain) that are able to bind to their
cognate ligand, and these are generally expressed only
by glial cells during development. Differential splicing
also leads to differences in the extracellular domains,
and these can influence ligand binding.
Several lines of evidence indicate that Trk receptors
do mediate a survival signal when bound to neu-
rotrophin. A mutant line of PC12 cells that lack TrkA
protein are unresponsive to NGF, but they can be
rescued if they are transfected with expression vectors
encoding the full-length rat trk cDNA (Figure 7.15).
Perhaps the most compelling evidence is that trans-
genic mice lacking Trk receptors display extensive
death in specific neuron populations (Figure 7.13).
TrkA -/- mice exhibit large-scale cell death in sympa-
thetic and dorsal root ganglia, in agreement with
earlier experiments that eliminated NGF with func-
tion-blocking antibodies (Smeyne et al., 1994). Tar-
geted disruption of the trkB gene in mice seems to be
particularly devastating in that all mice die within two
days of birth. Several peripheral populations are
affected, such as the trigeminal, nodose, and vestibu-
lar ganglia. In contrast, TrkC receptor deletion leads to
a 50% loss of cochlear ganglion neurons but spares
most nodose and trigeminal neurons. The develop-
mental effects of eliminating a neurotrophin or its
cognate Trk receptor are not necessarily identical
(Klein et al., 1993; Smeyne et al., 1994). For example,
the cell death that results from TrkB disruption could
be quantitatively greater than BDNF disruption
because TrkB also serves as a receptor for NT-4/5.
Expression of TrkB and TrkC is widely distributed
in the CNS, and levels remain quite high into adult-
hood (Barbicid, 1994). However, there is little evidence
that central neurons depend on neurotrophin signal-
ing for survival during development. Cholinergic cells
of the basal forebrain are NGF-sensitive, and exoge-
nous NGF is able to keep them alive when their axons
are cut (Gage et al., 1988). In addition, trkA -/- mice
have fewer axonal projections from cholinergic basal
forebrain neurons to the hippocampus and cortex, sug-
gesting a role in process outgrowth (see Chapter 4). In
trkB -/- or trkB/trkC -/- mice, increased apoptosis has
been reported in the developing hippocampus, cere-
bellum, cortex, striatum, and thalamus. However, this
is not necessarily associated with the period of natu-
rally occurring cell death (Minichiello and Klein, 1996;
Alcantara et al., 1997).
A
NGF
P
P
P
P
P
P
PC12 Cells
B
RTK
P
P
3T3 Cells
C
DRG cells
D
NGF
NGF
PC12 Cells (P140 +/+) PC12 Cells (p140 -/-)
FIGURE 7.15 The high-affinity NGF receptor was discovered
through a series of disparate observations. A. NGF was found to
elicit protein phosphorylation in PC12 cells. B. The oncogene in a
cancer cell line was found to be a transmembrane receptor tyrosine
kinase (RTK). C. The messenger RNA for this RTK was found in
extremely high levels in DRG neurons. D. When this RTK, called
p140, was eliminated from PC12 cells, they became unresponsive to
NGF. (Adapted from Maher, 1988; Martin-Zanca et al., 1986; Martin-
Zanca et al., 1990; Loeb et al., 1991)
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