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involved in song production (Tekumalla et al., 2002).
Interestingly, the EcR is almost identical to the thyroid
Endocrine signals have also been implicated in cell
survival among the sexually dimorphic telencephalic
nuclei of songbirds: those species where males learn to
produce mating calls, while females vocalize little, if at
all. In canaries and zebra finches, at least three areas of
the brain that support song production are much
larger in males than females (Nottebohm and Arnold,
1976). In some nuclei such as the robustus nucleus of
the archistriatum (RA), which shares some features
with motor cortex, the differences in neuron number
arise from a selective loss of cells in the female
(Nordeen and Nordeen, 1988; Kirn and DeVoogd,
1989). What is the evidence that steroid hormones
influence cell survival in males? If developing females
are treated with testosterone or its active metabolite,
estrogen, then the number of neurons in RA becomes
masculinized, and the birds acquire male-like vocal-
izations (Gurney, 1981). This effect is mediated by
androgen receptor since it can be prevented with a spe-
cific antagonist, Flutamide (Grisham et al., 2002). More
recently, the idea that steroid hormones can account
for sexual dimorphism of songbird vocal nuclei has
been challenged. For example, when genetic females
are “engineered” to grow testicular tissue that secretes
androgens, their vocal nuclei do not become mas-
culinized (Wade and Arnold, 1996). Therefore, there
are strong reasons to think that steroid hormones play
a role in control of cell number in male and female
songbirds, but the precise mechanisms remain elusive
(see Chapter 10).
C. elegans , most of them being neurons, but inactiva-
tion of two specific genes (called ced-3 and ced-4 )
rescues all of these cells, including neurons (discussed
in more detail below). Is it possible that neuron cell
death can actually be prevented by blocking protein or
RNA synthesis?
This hypothesis was tested by asking whether
neurons are rescued by protein synthesis inhibitors. As
described above, embryonic sympathetic neurons are
able to survive in vitro when grown in the presence of
NGF. When NGF is removed from the culture media,
few neurons remain after two days. Therefore, the first
experiment determined whether inhibitors of RNA or
protein synthesis could save NGF-deprived neurons
(Figure 7.21). Actinomycin-D blocks transcription by
binding to DNA and preventing the movement of
RNA polymerase, while cycloheximide prevents trans-
lation by blocking the peptidyl transferase reaction
on ribosomes. Each of these treatments completely
rescued sympathetic neurons following NGF depriva-
tion, demonstrating that new RNA and proteins must
be manufactured to bring about cell death. To deter-
mine when the harmful phase of translation occurs,
cycloheximide was delivered at several times after
NGF deprivation, and it was found that the cell death-
promoting proteins are produced at about 18 hours
(Martin et al., 1988). If all the molecular machinery for
cell death was present in the cytoplasm, one would
expect that neurons would be committed to die within
a few hours.
To determine whether mRNA and protein synthesis
are general features of cell death in vivo, animals were
treated with synthesis inhibitors at the age when
neurons are normally lost (Figure 7.21). When chick
embryos are treated with either cycloheximide or acti-
nomycin D on embryonic day 8, the time of maximum
motor neuron and DRG cell death, they exhibit a strik-
ing reduction in the number of dying neurons (Oppen-
heim et al., 1990). Similarly, the cell death that occurs
in response to declining levels of 20-HE in moths can
be reduced by RNA or protein synthesis inhibitors
(Fahrbach et al., 1994). These studies suggest that
trophic signals may stimulate the production of pro-
teins that protect the neuron from death, and in the
absence of a trophic signal harmful proteins may be
synthesized. The search for such proteins is discussed
Much of the cell death machinery seems to be
present at all times in a neuron's cytoplasm. However,
there is good evidence from several neuronal systems
that transcription or translation is necessary to acti-
vate this existing machinery. In fact, recent studies
have shown that, under certain conditions, cells can
undergo apoptosis even if their nucleus is removed, or
One might suppose that when a neuron is deprived
of a trophic factor, it fails to maintain normal levels of
synthesis and metabolism, and simply “passes away.”
In fact, neurons collaborate in their own death by acti-
vating genes and synthesizing protein that injure the
cell. That is, they “commit suicide.” The first indica-
tion that an active process could account for cell death
came from studies of nonneuronal cells. For example,
cultured tadpole tail cells die when exposed to thy-
roxine, but this can be prevented by blockers of RNA
and protein synthesis (Tata, 1966). A major break-
through came from genetic studies of cell death in the
nematode, Caenorhabditis elegans (Driscoll and Chalfie,
1992). About 10% of cells die during development in
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