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 C. elegans. Genetically
egl-1 acts downstream of or in parallel to
ces-2 and
ces-1, genes involved in cell-death specification (3), and upstream of or in parallel to
ced-9,
ced-4, and
ced-3, three genes that define the general cell-death machinery of C. elegans (4). 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 (5). 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. 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. Ellis, R. E. and H. R. Horvitz. (1991). Development 112, 591-603. 4. Horvitz, H. R., Shaham, S. and M. O. Hengartner. (1994). Cold Spring Harbor Symposia on Quantitative Biology LIX, 377-385. 5. Rinkenberger, J. L. and S. J. Korsmeyer. (1997). Curr. Op. Gen. Dev. 7, 589-596.