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its receptors accelerated, it became difficult to recon-
cile why other survival factors had not been found for
the many other cells that die during development.
Whereas scientists were vigorously searching for even
a single endogenous neuron survival factor in 1980,
there is now evidence that many families of factors
and receptors influence survival. Unfortunately, the
trophic influence of most factors has been tested in rel-
atively few brain regions. Of the neurons that have
been investigated, most are influenced by more than
one trophic factors, and the array of factors (or recep-
tors) can vary during the course of development.
In recent years, several cytokines have been found
to keep neurons alive in dissociated primary culture.
Cytokines are a diverse family of secreted proteins that
were originally discovered as growth factors in lym-
phocyte cultures, and many of these have turned out
to have a primary role in neuron survival as well. The
names of individual cytokines derive from the first bio-
logical activity that they were discovered to have, such
as killing tumors (tumor necrosis factor) or promoting
mitosis of hematopoietic stem cells (colony stimulat-
ing factor). One of the most thoroughly studied
cytokines, Ciliary neurotrophic factor (CNTF), sup-
ports the in vitro survival of autonomic, DRG, hip-
pocampal, and motor neurons. CNTF binds to an
intrinsic membrane protein, called CNTFR a, and this
binding event recruits two other transmembrane pro-
teins (gp130 and LIFRb) that form the b subunit of the
receptor complex (Figure 7.19). The a subunit provides
specificity to the trimeric receptor, while the b subunits
are responsible for signal transduction (Sleeman et al.,
2000). When the receptor complex forms, a tyrosine
kinase (member of the Jak family) that is associated
with the cytoplasmic tail of each b subunit becomes
activated, and phosphorylates a DNA-binding protein
(p91) that translocates to the nucleus and activates
transcription (Bonni et al., 1993).
In contrast to CNTF, the TGF-b family of cytokines
and their receptors seem to be involved in promoting
the death of sympathetic, sensory and motor neurons
in chicks. When all three isoforms of TGF-b were neu-
tralized with antibody treatment in vivo, virtually all
of the normally occurring cell death was prevented
(Krieglstein et al., 2000).
The influence of newly discovered factors on motor
neuron survival is of particular interest because nor-
mally occurring cell death in this population has been
well characterized and closely linked to the target
(Figures 7.6 and 7.9). When chick embryos are treated
with human recombinant CNTF, half of the naturally
occurring motor neuron death is prevented (Oppen-
heim et al., 1991). Surprisingly, parasympathetic, sym-
pathetic, and sensory neuron cell death is unaffected.
Although CNTF knockout mice display little effect on
cell survival during development, including motor
neurons, the functional loss of CNTF receptors does
increase cell death. Loss of CNTFRa increases motor
neuron death by about a third, and similar observa-
tions have been made on LIFRb and gp130 knockout
mice (DeChiara et al., 1995; Li et al., 1995; Nakashima
et al., 1999). This result implies that there is at least one
target-derived cytokine that supports motor neuron
survival through activation of the CNTFRa. In fact,
cardiotrophin-1 (CP-1) a cytokine that is expressed in
embryonic skeletal muscle, contributes to the survival
of embryonic motor neurons. CP-1 deficient mice
display 20-40% greater motor neuron loss during the
normal period of cell death. However, CP-1 does not
bind to CNTFRa, and so the hunt continues for the
A
CNTF
LIFR b
gp130
Jak
CNTFR
a
B
GDNF
Neurturin
RET
tyrosine
kinase
a
FIGURE 7.19 Survival factors and receptors in the nervous
system. A. Cytokine signaling: CNTF binds first to an intrinsic mem-
brane protein called CNTFRa. This event causes two other trans-
membrane proteins, gp130 and LIFR, to form the b subunit of the
receptor complex. The activated receptor complex signals via a tyro-
sine kinase (Jak) that is associated with the cytoplasmic tail of each
b subunit. B. GDNF signaling: GDNF and Neurturin bind first to
their cognate GFRa receptor. This complex then recruits the recep-
tor tyrosine kinase, RET, to homodimerize and to become autophos-
phorylated, leading to intracellular signaling.
GFR 1
a
GFR 2
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