Programmed Cell Death in DevelopmentProgrammed 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 by macrophages. Signals that can trigger apoptosis can include lineage information, damage due to ionizing radiation or viral infection or 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 cells). This might be accomplished by harnessing tumor necrosis factor (TNF), which triggers apoptosis in some target cells.
Recognition of PCD as a developmental mechanism dates back to the 1930's. Developmental processes that involve PCD include:
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. These topics are discussed in "A Brief Introduction to Apoptosis".
Now that we have discussed the apoptotic mechanism, we shall address the question of how the death sentence is delivered, and - if delivered - how cells can avoid it to gain a reprieve. Genetic studies on Drosophila have led to the identification of a gene called reaper, which plays a central role in initiation of cell death (White et al., 1994). reaper transcripts are found in doomed cells, and their presence precedes morphological manifestations of apoptosis by 1 to 2 hours (Figs. 8 and 9, White et al., 1994). The reaper gene apparently encodes a small peptide with no known homologies to known proteins. Deletions of reaper suppress apoptosis in response to apoptotic stimuli. Thus, reaper mutant embryos contain many extra cells (Fig. 2, White et al., 1994). reaper embryos have an intact apoptotic pathway that fails to be initiated. As shown in Figure 10 (White et al., 1994), reaper is thought to integrate the information from diverse signaling pathways and put a cell on the apoptotic pathway. At this point, the presence of reaper homologues in other organisms is unknown.
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. 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.
Barinaga, M. 1996. Forging a path to cell death. Science 273: 735-737.