*Divisions of Genetics and Endocrinology, Children’s Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. ‡ Broad Institute of Harvard and Massachusetts Institute of Technology, One Kendall Square, Massachusetts 02139, Cambridge, USA. § University of Zurich, Institute of Molecular Biology, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Correspondence to M.O.H. e-mail: michael. hengartner@molbio.unizh.ch doi:10.1038/nrm1836 Autophagy A pathway for the recycling of cellular contents, in which materials inside the cell are packaged into vesicles and are then targeted to the vacuole or lysosome for bulk turnover. Developmental apoptosis in C. elegans : a complex CEDnario Guillaume Lettre* ‡ and Michael O. Hengartner § Abstract | Apoptosis, an evolutionarily conserved programme of cellular self-destruction, is essential for the development and survival of most multicellular animals. It is required to ensure functional organ architecture and to maintain tissue homeostasis. During development of the simple nematode Caenorhabditis elegans, apoptosis claims over 10% of the somatic cells that are generated — these cells were healthy but unnecessary. Exciting insights into the regulation and execution of apoptosis in C. elegans have recently been made. These new findings will undoubtedly influence our perception of developmental apoptosis in more complex species, including humans. A tight balance between cell division and cell death is a fundamental principal of metazoan development: morphogenetic programmes are often characterized by high rates of cell proliferation, which are soon followed by waves of cell death (reviewed in REF. 1). Elimination of the webbing between digits in humans and mice, and the deletion of mammary tissue in males are good examples of this pattern. Developmental cell death can also have homeostatic functions, or can be used to eliminate aberrant, damaged or harmful cells (reviewed in REFS 2–5). Although several forms of cell death have been described in multicellular organisms 3 , for the purpose of this review we will focus exclusively on apoptosis, a gene-directed cellular self-destruction programme that generally serves biologically mean- ingful functions. Apoptotic cells usually present char- acteristic morphological changes, including chromatin condensation and DNA laddering, loss of mitochon- drial-membrane potential and of plasma-membrane phospholipid asymmetry, and detachment from the cellular matrix 6–8 . Apoptosis is an important, but not the sole, form of ‘programmed’ cell death that occurs during metazoan development. For example, recent studies have shown that autophagy can also contribute to developmental cell death (reviewed in REF. 9). Developmental apoptosis has been studied in all the main model systems of developmental biology, includ- ing the nematode Caenorhabditis elegans, the fruitfly Drosophila melanogaster and the mouse Mus musculus. Knowledge that was gained from these model organ- isms greatly contributed to our knowledge of apoptosis. For example, pioneering work in C. elegans established that apoptotic cell death is under genetic control and that this molecular programme is conserved throughout evolution 10,11 . Here, we focus our attention once again on this small invertebrate, and review some of the most exciting recent findings concerning the regulation and execution of developmental apoptosis in C. elegans. We hope that lessons drawn from C. elegans can guide, or at least inspire, apoptosis research in other systems. As dysregulation of apoptosis is associated with several human pathologies, such as cancer and neurodegenera- tive disorders, a better understanding of developmental apoptosis in C. elegans could also have interesting prog- nostic and therapeutic implications. In the following sections, we will discuss in more detail the various molecules that control apoptosis dur- ing C. elegans development. We begin with a description of the C. elegans core apoptotic machinery, and present a molecular model of how apoptosis is triggered in C. elegans. We then discuss the complexity of the regu- lation of developmental apoptosis in C. elegans, using three cell types as examples. Finally, we highlight some pertinent, but still unanswered, questions concerning apoptosis in this organism. Engulfment of apoptotic cells and apoptotic DNA degradation, topics that each consti- tute a field of their own, will not be covered extensively here (see BOX 1 and REFS 12–14). Apoptosis during development The development of C. elegans is invariant: reproducible patterns of cell division, cell death and cell migration give rise to animals with exactly the same number of cells and an invariant anatomy. Apoptotic cell death is a com- mon cell fate in C. elegans 15–17 : out of the 1,090 cells that are generated to form an adult hermaphrodite, exactly DEVELOPMENTAL CELL BIOLOGY REVIEWS NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 7 | FEBRUARY 2006 | 97