21.5 Cell Death and Its Regulation

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EXPERIMENTAL FIGURE 21-32 A web-footed chicken. During the development of many vertebrate limbs, cells in the soft tissue between the embryonic digits undergo programmed cell death. In the chicken foot, this process leads to the formation of four separate toes (left). During chicken foot development, bone morphogenetic proteins (BMPs) (members of the TGF-β superfamily of hormones; see Figure 16-3) are expressed by interdigital cells and induce apoptosis. In this experiment, a dominant-negative type I BMP receptor was expressed in a developing chicken foot, blocking BMP signaling and preventing the programmed cell death that normally occurs. This manipulation allowed the survival of cells that then divided and differentiated into a web (right). The similarity of this webbing to webbed duck feet led to studies showing that BMPs are not expressed in duck interdigital cells. These results indicate that BMP signaling actively mediates cell death in the embryonic limb.
[Republished with permission of AAAS, from Zou, H. and Niswander, L., “Requirement for BMP signaling in interdigital apoptosis and scale formation,” Science, 1996, 3;272(5262):738–41; permission conveyed through Copyright Clearance Center Inc.]

Regulated cell death is a counterintuitive, but essential, process in metazoan organisms. During embryogenesis, the programmed death of specific cells keeps chicken feet as well as our hands from being webbed (Figure 21-32); it also prevents our embryonic tails from persisting and our brains from being filled with useless nerve connections. In fact, the majority of cells generated during brain development subsequently die. We will see in Chapter 23 how immune-system cells that react to normal body proteins or produce nonfunctional antibodies are selectively killed. Many kinds of muscle, epithelial, and white blood cells constantly wear out and need to be removed and replaced.

Cell-cell interactions regulate cell death in two fundamentally different ways. First, most, if not all, cells in multicellular organisms require specific protein hormone signals to stay alive. In the absence of such survival signals, frequently referred to as trophic factors, cells activate a “suicide” program. Second, in some developmental contexts, including the immune system, other specific hormone signals induce a “murder” program that kills cells. Whether cells commit suicide for lack of survival signals or are murdered by killing signals from other cells, cell death is most often mediated by a common molecular pathway, termed apoptosis, that is largely conserved in invertebrates and vertebrates. The cell corpses are ingested by neighboring calls, and their contents are broken down into small molecules and reused to build other cells.

A different form of cell death, necrosis, occurs when cells are subjected to injury or excessive stresses such as heat, absence of oxygen, or infection by pathogens. Necrosis creates holes in the plasma membrane, causing leakage of intracellular contents. Perhaps surprisingly, one form of necrosis, termed necroptosis, is often triggered by extracellular hormones such as tumor necrosis factor alpha (TNFα; see Figure 16-35). Activation of this cell-death pathway frequently causes inflammation and contributes to the development of many human diseases, including nerve degeneration and atherosclerosis.

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In this section, we first distinguish programmed cell death from death due to necrosis and then describe how genetic studies in the nematode worm C. elegans led to the elucidation of an evolutionarily conserved effector pathway that leads to cell suicide. We then turn to vertebrates, in which cell death is regulated both by trophic factors, as exemplified by their importance in programmed cell death in neuronal development, and by cell stresses such as DNA damage. We illustrate the key roles of mitochondria in initiating vertebrate cell-death pathways. Finally, we discuss necroptosis and how our understanding of this process has paved the way for treating certain human diseases.