Programmed Cell Death in Animal Development

condense, and the organelles and plasma membrane retain their integrity in a process Kerr and his colleagues and Martin C. Raff Developmental Neurobiology Programme named apoptosis. The dead cells or their fragments are rapidly phagocytosed by neighboring cells or macro-phages before there is any leakage of the contents of the cells, and thus they do not induce an inflammatory London, WC1E 6BT United Kingdom response. Apoptotic cells in developing tissues are almost always inside other cells (Figures 1A–1C), suggesting that dying cells are usually phagocytosed before they display the morphological changes of apoptosis. Programmed cell death (PCD) occurs during the devel-Because apoptotic cell deaths usually look so similar opment of all animals that have been studied, but only from tissue to tissue and animal to animal (Figures 1A– recently has its molecular basis been discovered. In this 1C), Kerr and his colleagues proposed that these deaths review, we briefly consider some of the main events reflect the operation of an active, intracellular death pro-in the history of PCD in animal development. We then gram that can be activated or inhibited by a variety of summarize what has been learned about the molecular physiological or pathological environmental stimuli. mechanism of PCD and some of the intracellular pro-It took almost another 20 years, however, before the teins that control it. We next discuss the functions of idea that animal cells have a built-in death, or suicide, PCD in development and how PCD is regulated during program became generally accepted, largely through development by signals from other cells. Finally, we genetic studies in the nematode Caenorhabditis elegans consider what the evolutionary origins of PCD may have that identified genes that seem dedicated to the death been. program and its control (Horvitz et al., 1982; Ellis and Horvitz, 1986), and then through the finding that some Some History of these genes were homologous to mammalian genes Soon after it was recognized in the middle of the last (Yuan et al., 1993; Hengartner and Horvitz, 1994). With century that organisms are made of cells, it was discov-this acceptance, the term programmed cell death (PCD) ered that cell death can be an important part of animal has come to have a different meaning from its original. development (reviewed in Clarke and Clarke, 1996). First It now generally refers to any cell death that is mediated observed during amphibian metamorphosis (Vogt, by the intracellular death program, no …