Gain-of-function (gf) mutations in the gene
egl-1 (egl, egg-laying defective) cause the hermaphrodite-specific neurons (HSNs) to inappropriately undergo programmed cell death in hermaphrodites (1, 2). In a screen for dominant suppressors of the
egl-1(gf) phenotype, we identified a loss-of-function (lf) mutation in
egl-1. The
egl-1(lf) mutation prevents not only the deaths of the HSNs but also most if not all of the somatic cell deaths that occur during development. Thus,
egl-1 is required for programmed cell death in somatic tissues of C. elegans (3). Genetically
egl-1 acts downstream of or in parallel to
ces-2 and
ces-1, genes involved in cell-death specification (4), and upstream of or in parallel to
ced-9,
ced-4, and
ced-3, three genes that apart from
egl-1 define the general cell-death machinery of C. elegans (5). The EGL-1 protein contains a BH3-like (BH3, Bcl-2 homology region 3) domain, suggesting that EGL-1 may be a member of a recently identified family of cell-death activators that include the mammalian proteins Bik, Bid, Harakiri, Bad, Bim, and Blk (6). Genetic and biochemical evidence suggests that EGL-1 functions directly through CED-9, a cell-death antagonist similar in sequence and function to the mammalian proto-oncogene and cell-death antagonist Bcl-2. We propose that EGL-1 induces cell death by binding to and antagonizing the ability of CED-9 to block cell death. Thus
egl-1 encodes the most upstream component of the general cell-death machinery in C. elegans and may function through an evolutionarily conserved mechanism. Programmed cell death not only occurs in somatic tissues during the embryonic and postembryonic development of C. elegans but also in the germline of adult hermaphrodites (7).
ced-9,
ced-4, and
ced-3 appear to be required for the programmed cell death of germ cells (8). In contrast,
egl-1 is not involved in this process which suggests that programmed cell death in somatic tissues and in the germline are regulated and initiated by two different pathways, an
egl-1-dependent pathway and an
egl-1-independent pathway. 1. Trent, C., Tsung, N., and H. R. Horvitz. (1983). Genetics 104, 619-647. 2. Ellis, H. and H. R. Horvitz. (1986). Cell 44, 817-829. 3. Conradt, B. and H. R. Horvitz. (1998). Cell 93, 519-529. 4. Ellis, R. E. and H. R. Horvitz. (1991). Development 112, 591-603. 5. Horvitz, H. R., Shaham, S. and M. O. Hengartner. (1994). Cold Spring Harbor Symposia on Quantitative Biology LIX, 377-385. 6. Rinkenberger, J. L. and S. J. Korsmeyer. (1997). Curr. Op. Gen. Dev. 7, 589-596. 7. Sulston, J. (1988). The Nematode Chaenorhabditis elegans. Cold Spring Harbor Laboratory Press. 123-155. 8. Hengartner, M. O. (1997). C. elegans II. Cold Spring Harbor Laboratory Press. 383-415.