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In-Depth Information
NGF
NT-3
BDNF
NT-4/5
proNGF
LIGAND
RECEPTOR
TrkA
TrkC
TrkB
p75
CELL DEATH
FOLLOWING
RECEPTOR
ELIMINATION
70% DRG
95% SCG
70% trigeminal
0% cochlear
0% vestibular
basal forebrain
atrophy
20% DRG
0% SCG
20% trigeminal
50% cochlear
15% vestibular
30% DRG
50% DRG
60% trigeminal
15% cochlear
60% vestibular
90% nodose
basal forebrain
cerebellum
FIGURE 7.13 Neurotrophins and their receptors. Following the discovery of NGF, several homologous
proteins were found, including NT-3, BDNF, and NT-4. Each of these proteins binds selectively to a member
of the Trk receptor tyrosine kinase family, as illustrated. In addition, there is a low-affinity receptor, called
p75 NTR . The effect of eliminating the neurotrophin or its receptor in mice is shown beneath each pair.
reduced death in
cholinergic forebrain
recent additions to the family have been given the less
colorful names: neurotrophin-3 (NT-3), NT-4/5, NT-6,
and NT-7; the latter two are found only in fish (Figure
7.13). In each case, a precursor protein of about 250
amino acids, called the proform , is processed post-
translationally to produce active peptides of about 120
amino acids. These peptides form homodimers and
become biologically active. The family members share
about 50% sequence homology with one another, par-
ticularly within six hydrophobic regions that are
responsible for linking the two protomers together.
Each neurotrophin also contains a unique amino acid
sequence, and it is this variable region that is respon-
sible for binding to a specific receptor (Ibanez, 1994).
Each of the neurotrophins has been shown to play
a role in the survival of specific peripheral neuron pop-
ulations. As with NGF, two general classes of experi-
ment have been performed: One can provide excess
neurotrophin (in vivo or in vitro), or one can decrease
the amount of endogenous neurotrophin, commonly
by single-gene knockout experiments (Chapter 2).
These experiments indicate that BDNF is a necessary
endogenous signal for the survival of vestibular
ganglia, while NT-3 is an endogenous survival signal
for the cochlear ganglion. A comparison between the
two types of experiments also show that positive
results must be treated cautiously. While BDNF is able
to save chick motor neurons when administered
during the period of naturally occurring cell death,
there is no effect on motor neuron survival in BDNF
knockout mice (Oppenheim et al., 1992; Ernfors et al.,
1994, 1995). Both BDNF and NT-3 also contribute to the
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