Worm Breeder's Gazette 7(2): 44

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More on Cell Death Mutants

H.M. Ellis, B. Horvitz

Figure 1

In the last Newsletter [7(1)] we described the identification of the 
gene ced-3, which appears to be necessary for the initiation of 
programmed cell death in C.  elegans.  We have constructed double 
mutants involving ced-3 and three previously identified genes known to 
affect cell deaths: ced-1 and ced-2 mutants prolong the highly 
refractile stage of cell death (Ed Hedgecock, personal communication), 
and nuc-1 mutants fail to degrade the DNA of dying cells and result in 
the persistence of pycnotic nuclei (John Sulston, personal 
communication).  The epistasis of ced-1 and ced-2 over nuc-1 and of 
ced-3 over all three other genes suggests that these genes act 
sequentially in a developmental pathway for programmed cell 
[See Figure 1]
We believe that this program is expressed by most cells that undergo 
programmed cell death, but there may be exceptions.  For example, the 
death of the male linker cell, which requires the presence of a 
'killer cell' (Sulston et al., Develop.  Biol.  78: 542, 1980), can 
occur in ced-3 mutants.  Perhaps ced-3 is required only for deaths 
that are cell autonomous.
At least some cells that survive in ced-3 mutants differentiate.  We 
previously noted that the postdeirids of ced-3 animals contain 
supernumerary dopaminergic neurons (presumably the cells that die in 
wild type) and that the male-specific cephalic companion neurons (the 
homologues of which die in wild-type hermaphrodites) appear to survive 
and express normal characteristics in ced-3 hermaphrodites.  More 
recently we have obtained evidence that two additional classes of 
surviving cells differentiate in ced-3 animals.  First, ced-3 mutants 
contain supernumerary pharyngeal serotonergic neurons: in ced-3 
animals four pharyngeal cells have a serotonin-uptake system, whereas 
in wild-type animals only two neurons, known as the NSM's, accumulate 
exogenous serotonin (Horvitz et al., Science 216: 1012, 1982).  John 
Sulston has found that the embryonically-generated NSM's are the 
sisters of cells that die in N2, which suggests that the extra 
serotonin cells in ced-3 animals may be the sisters of the NSM's.  
Second, the hermaphrodite-specific neurons (HSN's), the homologues of 
which die in wild-type males, appear to survive and express normal 
characteristics in ced-3 males.
Carol Trent has recently isolated a number of Egl (egg-laying 
defective) mutants that lack HSN function (see Trent, Tsung and 
Horvitz, this Newsletter).  Two of these mutants, egl-1(n487) V and 
n695 V, have no HSN's at hatching.  Both of these mutations are 
dominant and are suppressed by ced-3.  ced-3; 
lay eggs and have HSN's, suggesting that the 
Egl phenotype of egl-1 reflects the expression in hermaphrodites of 
the normally male-specific program for HSN cell death.  That ced-1; 
odite embryos have supernumerary cell deaths 
when and where the HSN-homologues die in wild-type males supports this 
interpretation (we used ced-1 to facilitate the identification of 
these cells).  ced-3; 5) animals have HSN's; 
however, other phenotypes associated with n695 (see Trent and Horvitz, 
this Newsletter) are not suppressed by ced-3.  We are currently 
generating Egl+ revertants of eg1-1 to isolate additional ced-3 
alleles as well as mutations in other genes that block programmed cell 

Figure 1