| In C. elegans, as in mammals, cells which are about to undergo apoptosis are rapidly engulfed by phagocytes. In order to understand the molecular nature of such apoptosis-triggered phagocytosis, a study was made on ced-6, which is one of seven engulfment genes found in C. elegans. Phenotypic study showed that ced-6 is required to remove both somatic and germline apoptotic cells. Since no other obvious phenotypes of ced-6 have been observed, the role of this gene appears to be specific to apoptosis-triggered engulfment. ced-6 was cloned using a positional cloning method. The CED-6 protein was found to contain a phosphotyrosine binding (PTB) domain, a coiled-coil domain, and several potential SH3 binding sites. Genetic mosaic analysis demonstrated that ced-6 acts within engulfing cells. Thus, CED-6 might be an adaptor molecule functioning in a tyrosine kinase pathway, a novel pathway that is required specifically for the removal of apoptotic cells. In mammals, many receptors have been identified to be involved in recognizing apoptotic cells; these receptors have been proposed to act at different stages of apoptosis. In this study, the signal transduction pathway in which ced-6 is involved has been shown to promote the removal of dying cells at a very early stage of apoptosis, as well as at the stage of persisting cell corpses. A genetic study placed ced-6 downstream of both ced-1 and ced-7. This result, together with previously published genetic data, also suggests that ced-1, -6, and -7 might function in the same signal transduction pathway.; The ced-6 signal transduction pathway might be conserved throughout the animal kingdom, as a few EST clones from C. briggsae, Drosophila, and human were identified. The translation products from these EST clones are very conserved with the CED-6 protein within the PTB domain. A putative full-length human ced-6 cDNA was later isolated. Like the C. elegans CED-6, the human CED-6 also contains a PTB domain, a coiled-coil domain, and several potential SH3 binding sites. Overexpression of the human ced-6 in C. elegans rescues significantly the engulfment defect of ced-6 in both soma and germline. This study also shows that human CED-6 is expressed in most, if not all, human tissues. Thus, human CED-6 might be a functional homologue of the C. elegans. CED-6, and that the signal transduction pathway in which CED-6 is involved might be a fundamental process in metazoan. |
