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the neural crest, are unresponsive to NGF treatment.
In the DRG, only small peptidergic neurons that carry
nociceptive signals to the spinal cord are killed fol-
lowing loss of the NGF signal. More recently, it has
been possible to reproduce the effects of antibody
treatment in genetically engineered mice. When a dele-
tion is made in the coding sequence of the NGF gene,
homozygous animals display profound cell loss in
both sympathetic and sensory ganglia (Crowley et al.,
1994).
If NGF is the endogenous survival factor, then it is
important to verify its presence at the sympathetic
and sensory ganglion target regions at an appropriate
time during development. Although NGF levels are
extremely low (except in the fortuitous case of the male
mouse salivary gland, from which it was purified), it
has been possible to localize the protein with immuno-
histochemical staining and the NGF mRNA with in
situ hybridization. For example, trigeminal axons
arrive at their cutaneous target just before the NGF
mRNA and protein are manufactured, and the initial
outgrowth of trigeminal axons is NGF-independent
(Davies et al., 1987), suggesting that the maintenance
of trigeminal neurons depends on NGF derived from
their target. The success with NGF was achieved by
1960, and the expectation was that many other neu-
rotrophic substances would quickly be found in the
central nervous system. While several growth and sur-
vival factors were discovered in nonneuronal systems,
the search for another bona fide neurotrophic sub-
stance was, at first, somewhat frustrating.
Sarcoma
DRG
DRG
Control experiment
Snake venom used to
digest nucleic acid
Snake venom
alone
FIGURE 7.12 A soluble factor that supports the survival and
growth of DRG neurons is discovered in a mouse sarcoma and, later,
in snake venom. (Left) DRG neurons obtained from chick embryos
were placed in a tissue culture dish, and conditioned medium from
a mouse sarcoma was added. The venom of a snake was added to
the culture to determine whether nucleic acids mediate the trophic
effects. The DRG neurons survived and grew processes under these
conditions. (Right) When the control experiment was performed, in
which only snake venom was added to the DRG neuron cultures, a
surprising discovery was made. The DRG neurons survived and
grew, indicating that the snake venom must also have contained a
soluble survival factor. (Adapted from Cohen and Levi-Montalcini,
1956; Levi-Montalcini and Cohen, 1956)
THE NEUROTROPHIN FAMILY
The full amino acid sequence of NGF was obtained
by 1971, yet a decade elapsed before a second neu-
rotrophic factor was identified. The search began with
the simple observation that, in contrast to its effect
on the retinae from lower vertebrates, NGF does not
stimulate neurite outgrowth from cultured rat retina.
Working under the assumption that there must be a
growth factor or factors for mammalian retina, a
soluble extract was prepared from the entire pig brain.
This extract did, in fact, stimulate retinal process out-
growth in a dose-dependent manner. When the active
substance, named brain derived growth factor (BDNF),
was purified and its amino acid sequence determined,
its structure displayed a striking similarity to that of
NGF (Turner et al., 1982; Leibrock et al., 1989).
Several members of the neurotrophin family have
now been isolated, and they are found in both the
peripheral and central nervous systems. The more
longer restricted to their normal synaptic target, but
grow widely in the peripheral field and can even
invade blood vessels or the central nervous system (see
Chapter 5).
In a second experiment to determine whether
endogenous NGF is necessary for survival, an anti-
body directed against the NGF protein was injected
into neonatal rodents. This leads to the loss of almost
all sympathetic neurons (Levi-Montalcini and Booker,
1960). It was later found that DRG cells are no longer
dependent on NGF at the age when antibody was
administered, but they can be destroyed by prenatal
exposure to NGF antibody (Johnson et al., 1978). In
fact, not all sensory neurons are dependent on NGF for
survival. Those sensory neurons that derive from
sensory placodes (e.g., nodose ganglion), rather than
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