The Molecular Mechanism of Programmed Cell Death in C. elegans

ABSTRACT Programmed cell death or apoptosis plays a fundamental role during animal development, metamorphosis, and tissue homeostasis. It is a genetically controlled physiological process that comprises two distinct and sequential processes: the death of cells, and their subsequent removal by engulfing cells. In the nematode C. elegans , genetic studies led to the discovery of 15 genes that function in programmed cell death 1 ( Fig. 1 ). These 15 genes have been divided into four groups based on the order of their activity during the process of programmed cell death: (1) those involved in the decision making ( ces‐1 and ces‐2 ); (2) in the process of execution ( ced‐3, ced‐4, ced‐9 and egl‐1 ); (3) in the engulfment of dying cells by engulfing cells ( ced‐1, ced‐2, ced‐5, ced‐6, ced‐7, ced‐10, ced‐12 ); and (4) those in the degradation of cell corpses within engulfing cells ( nuc‐1 ). In the last five years, several genes in the genetic pathway of programmed cell death have been shown to be conserved across a wide range of species; all genes involved in the step of execution in C. elegans have their corresponding mammalian homologs ( Fig. 2 ). Furthermore, emerging evidence from molecular studies of engulfment genes in several species suggests that the signaling process from apoptotic cells to engulfing cells and the subsequent engulfment process might be also conserved across species ( Table 1 ). The genetic pathway for programmed cell death in C. elegans . In the nematode C. elegans , genetic studies led to the discovery of 15 genes related to programmed cell death. These 15 genes have been divided into four groups based on the order of their activity during the process of programmed cell death: ces‐1 and ces‐2 are involved in the decision making, ced‐3, ced‐4, ced‐8, ced‐9 , and egl‐1 in the process of execution, ced‐1, ced‐2, ced‐5, ced‐6, ced‐7, and ced‐10 in the engulfinent of dying cells by engulfing cells, and nuc‐1 in the degradation of cell corpses within engulfing cells. Adapted from reference 1 . image Conservation of the execution step in the genetic pathway for programmed cell death. In C. elegans , the execution step in the genetic pathway for programmed cell death comprises four genes, ced‐3, ced‐4, ced‐9 , and egl‐1 . All of these genes have their corresponding mammalian homologs: CED‐9 is a member of the Bcl‐2 family, CED‐3 is a caspase family member, CED‐4 is homologous to the Apaf‐ 1 protein, and EGL‐1 is similar in structure to Bid and other BH3 domain only‐containing proteins. In Drosophila, reaper, hid , and grim are required for the apoptotic cell death and might act upstream of the Drosophila caspases, drICE, DREDD, and DCP‐1. The homologs of reaper, hid , and grim in other species have not been identified. Similarly, the homologs of EGL‐1, CED‐4 and CED‐9 in Drosophila have not been found. image Evolutionary conservation of engulfment genes a image