Programmed cell death in the nematode C. elegans

Programmed cell death is a common feature during animal development. In the nematode C. elegans, more than 12 genes have been identified that function in the apoptotic killing and elimination of 131 of the 1090 cells that are generated during hermaphrodite development. These genes divide the process of programmed cell death into three distinct steps: execution of the death sentence; engulfment of dying cells; and degradation of dead, engulfed cells. Biochemical characterization of the genes in this pathway has led to the identification of an apoptotic machinery that mediates apoptotic death in this species. The proximal cause of apoptosis in C. elegans is the activation of the caspase homolog CED-3 from the inactive zymogen (proCED-3) into the mature protease. This activation is mediated by the Apaf-1 homolog CED-4. In cells that should survive, CED-3 and CED-4 pro-apoptotic activity is antagonized by the Bcl-2 family member CED-9. CED-9 has been proposed to prevent death by sequestering CED-4 and proCED-3 in an inactive ternary complex, the apoptosome. In cells fated to die, CED-9 is, in turn, inactivated by the pro-apoptotic BH3 domain-containing protein EGL-1, likely through a direct protein-protein interaction. The structural and functional conservation of cell death genes between nematodes and mammals strongly suggests that the apoptotic program is ancient in origin and that all metazoans share a common mechanism of apoptotic cell killing.