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Programmed Cell Death in Development
Why must some cells die for the good of the embryo?
Programmed cell death (PCD) is an important mechanism in both development
and homeostasis in adult tissues for the removal of either superfluous,
infected, transformed or damaged cells by activation of an intrinsic suicide
program. One form of PCD is apoptosis, which is characterized by
maintenance of intact cell membranes during the suicide process so as to
allow adjacent cells to engulf the dying cell so that it does not release
its contents and trigger a local inflammatory reaction. Cells undergoing
apoptosis usually exhibit a characteristic morphology, including fragmentation
of the cell into membrane-bound apoptotic bodies, nuclear and cytoplasmic
condensation and endolytic cleavage of the DNA into small oligonucleosomal
fragments (Steller, 1995). The cells or fragments are then phagocytosed
Signals that can trigger apoptosis can include
- lineage information
- damage due to ionizing radiation or viral infection
- extracellular signals.
Extrinsic signals may either suppress or promote apoptosis, and the same
signals may promote survival in one cell type and invoke the suicide program
in others (Steller, 1995).
Invocation of the suicide program involves the synthesis of specific messenger
RNA molecules and their translation. PCD can sometimes be suppressed by
inhibiting transcription or translation (Steller, 1995), which provides
evidence that cell death is mediated by intrinsic cellular mechanisms.
Cell death is currently the subject of considerable research activity. This
interest stems, in part, from the potential for understanding oncogenesis
and the possibility of exploiting the cell death program for therapeutic
purposes. For example, inhibition of cell death might contribute to oncogenesis
by promoting cell survival instead of death. Likewise, triggering cell death
might provide the means for eliminating unwanted cells (e.g., tumor
Recognition of PCD as a developmental mechanism dates back to the 1930's.
Developmental processes that involve PCD include:
- Elimination of transitory organs and tissues. Examples include
phylogenetic vestiges (pronephros and mesonephros in higher vertebrates),
anuran tails and gills and larval organs of holometabolous insects.
- Tissue remodeling. Vertebrate limb bud development (Fig. 11.42,
Saunders, 1982; Fig. 1, Saunders, 1966) is an example. If PCD fails, in
formation of the digits, digits remain joined by soft tissue. Compare,
for example, the situation in the chick and duck hind limbs. If chick limb
mesoderm is combined with duck ectoderm, PCD fails and the digits remain
joined (Saunders, 1966). This observation implicates the ectoderm in providing
the signal to trigger PCD. Another example is formation of heart loops
during vertebrate development. Depletion of cells in spinal ganglia occurs
during development of the chick embryo. As shown in Table 11.1 (Saunders,
1982), there is precise chronological and spatial control over this process.
Interestingly, injections of nerve growth factor reduce the frequency of
cell death in the spinal ganglia. This observation provides a link between
growth control and PCD.
Much of our current knowledge about the molecular genetics of PCD comes
from work on Caenorhabditis elegans. The adult hermaphrodite C.
elegans forms 1090 somatic cells, of which 131 die by apoptosis. There
are four stages in apoptosis in worms (Steller, 1995):
- decision whether a cell should die or assume another fate;
- engulfment of the dead cell by phagocytes;
- degradation of the engulfed corpse.
A number of genes have been identified that regulate these processes
in worms (see Fig. 1, Steller, 1995). Mutations affecting the final three
stages affect all somatic cells, whereas genes affecting the death verdict
affect very few cells. Execution itself is mediated by ced-3, ced-4
and ced-9 (ced = cell death defective).
Cloning of the apoptotic genes of C. elegans and their characterization
have led to considerable understanding of the molecular events of apoptosis
and to the identification of mammalian homologues of the apoptotic effectors.
For example, ced-9 and ced-3 are homologous to the protooncogene
bcl-2 and ice (interleukin-1ß-converting enzyme, respectively.
Why do some cells die and others survive? There is evidence from work on
higher organisms that extrinsic signals may protect cells from apoptosis
by suppressing the suicide program (Raff, 1992). For example, the survival
of developing neurons may depend upon neurotrophic factors secreted by their
targets; a failure to receive sufficient stimulation results in death.
What is the advantage to the organism of using extrinsic signaling to sustain
cell survival? One possibility is that it could provide a simple system
to eliminate cells that end up in the wrong place; without a signal to sustain
them, rogue cells would be eliminated (Raff, 1992). Consider primordial
germ cells, for example. In mammals, they originate in the hindgut and must
migrate to the genital ridges, where they form the gametes. Those that fail
to reach the genital ridges are eliminated, presumably because they are
deprived of the signal (Steel factor) that is required for their survival
in the genital ridges (De Felici and Pesce, 1994).
A disadvantage to the organism of the mechanism that necessitates signaling
to prevent apoptosis is that its failure by mutation can lead to the survival
of unwanted cells, which - paradoxically - can lead to death of the organism
itself. On the other hand, an opportunity is presented by such a mechanism
to allow investigators to devise means for targeting unwanted cells for
destruction. This might be accomplished by harnessing tumor necrosis factor
(TNF), which triggers apoptosis in some target cells. Prostate cancer is
an example. The survival of prostate cells is dependent upon androgens;
androgen depletion leads to a reduction in cell number by apoptosis. Recently,
the dependence of prostate cells on androgens to avoid cell death has been
exploited therapeutically by the use of androgen ablation to invoke apoptosis
in prostate cancer cells and prolong survival in men with prostate cancer.
Significantly, resistance to androgen depletion correlates with overexpression
of bcl-2, the human ced-9 homologue that acts as a brake on
prostate cancer cell apoptosis (Raffo et al., 1995). Thus, escape
from androgen sensitivity by overexpression of bcl-2 in a subset
of prostate cancer cells leads to proliferation of these cells and, ultimately,
death of the patient. If bcl-2 could be down-regulated, apoptosis
of these cells could be invoked and the cancer controlled.
Ironically, there may be an inverse correlation between cell death and survival
of the organism. Exploitation of this relationship holds much promise for
therapeutic control of diseases such as cancer.
- What are the characteristics of apoptosis?
- What is the evidence that apoptosis is mediated by intrinsic cellular
- Discuss examples of apoptosis as a mechanism of morphogenesis.
- Describe the phases of cell death.
- What are the mammalian homologues of ced-9 and ced-3,
- Where in the cell death program do bcl-2, p53 and ICE function?
- How might interference with the cell death program be manifest?
Links to Related Material
A Brief Introduction to Apoptosis
Cell Death and Cancer
on the Net
Death Home Page
Journal Club :
- Discussion of Inhibition of Bax Channel-Forming Activity by Bcl-2
Authors: Antonsson, B., Conti, F., Ciavatta, A., Montessuit, S., Lewis,
S., Marinou, I., Bernasconi, L., Bernard, A., Mermod, J-J., Mazzei, G.,
Maundrell, K., Gambale, F., Sadoul, R., Martinou, J-J. Source: Science
Vol 277, July 18, 1997, pages 370-372.
Special Report on Apoptosis
A novel anti-apoptosis gene
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