During animal development, cells undergoing programmed cell death are rapidly engulfed and degraded by neighboring cells. The engulfment of apoptotic cells is an evolutionarily conserved process that prevents unwanted cells from releasing potentially harmful contents. Genetic studies C. elegans have identified seven genes,
ced-1, -2, -5, -6, -7, -10, and 12, that are required for efficient engulfment. These seven genes define two partially redundant pathways. In one pathway,
ced-1,
ced-6 and
ced-7 appear to act together to control cell-corpse recognition. CED-1 is a transmembrane receptor similar to a mammalian scavenger receptor SREC. CED-1 recognizes and clusters around cell corpses to mediate their engulfment.
ced-7 encodes an ABC transporter that promotes the recognition of cell corpses by CED-1, possibly by exposing phospholipids on the outer surface of the cell corpses.
ced-6 encodes an adaptor-like protein that acts in engulfing cells and may function as an adaptor to relay the engulfment signal downstream of CED-1. In the other pathway, CED-2 CrkII, CED-5 DOCK180, and CED-12 ELMO1 act in a protein complex to activate CED-10, a Rac GTPase. The activation of CED-10 Rac leads to the reorganization of the actin cytoskeleton and the extension of engulfing cell surface around cell corpses.. To identify new genes that control cell-corpse engulfment, we have performed two large-scale genetic screens for new zygotic or maternal-effect mutations that affect cell-corpse engulfment.
ced-12 was identified from one of the screens as a new engulfment gene, demonstrating that this approach is effective in discovering new genes. In addition, new alleles of previously identified genes
ced-1, -2, -5, -6, -7, -8, and 10 and
cup-5 have been isolated. Many mutants isolated define distinct phenotypic categories, some of which have not been described before. For example, 17 mutants display engulfment defects and embryonic lethality. These phenotypes indicate that the mutations affect not only engulfment but also certain essential cellular or developmental process, as cell-corpse engulfment is a non-essential event. The class of engulfment-defective and embryonic-lethal mutations has defined at least two new genes, one of which appears to act in the
ced-1 pathway and to be required for CED-1 to recognize cell corpses. We believe that further characterization of these mutations will help us understand the engulfment of cell corpses as well as other biological processes regulated by the same machinery.