Programmed cell death (apoptosis) plays a crucial role in animal development as well as in the elimination of damaged cells. The pathway underlying this process is evolutionarily conserved from worms to humans. An important step in apoptosis is the removal of dying cells from the organism via phagocytosis. In C. elegans , removal of dying cells proceeds via two partially redundant pathways. The first pathway is composed of two proteins at the cell membrane, CED-1/SREC and CED-7/ABC1, which may function in the recognition of the dying cell, and CED-6, a putative adapter protein. The second pathway is comprised of CED-2/CrkII, CED-5/Dock180, and CED-10/Rac1, thought to be involved in reorganization of actin filaments, which is required to extend the engulfing cell's membrane around the dying cell. We genetically and molecularly characterized a novel member of the
ced-2 /
ced-5 /
ced-10 pathway,
ced-12 . In C. elegans , CED-12 is required for the engulfment of dying cells and for various cell migrations. Positional cloning of
ced-12 revealed that this gene encodes a protein of 731 amino acids, the molecular function of which is unclear from the sequence analysis. However,
ced-12 is clearly conserved through evolution, possessing at least one homologue in Drosophila, and two in mice and humans. We have named the mammalian
ced-12 orthologues elmo (genes involved in e ngu l fment and mo tility), and refer to the products of these two
ced-12 orthologues as ELMO1 and ELMO2. In mammalian cells, ELMO-1 functions together with CrkII and Dock180 upstream of Rac1 during phagocytosis. ELMO-1 physically interacts with Dock180 and forms a ternary complex with CrkII, which appears necessary for the functional synergy between the two proteins during phagocytosis. ELMO-1 also regulates Rac-1 dependent cytoskeletal changes and localizes to membrane ruffles. Expression of ELMO-1 or ELMO-2 in CED-12 deficient worms significantly rescues the gonadal migration defect. These studies show that
ced-12 / elmo is an evolutionarily conserved upstream regulator of
ced-10 /Rac1 that affects engulfment and cell migration in both C. elegans and mammalian cells.