Programmed cell death (PCD) is an important process during animal development and tissue homeostasis to clear away unnecessary or abnormal cells. One notable example is the sexually dimorphic process in which cells or organs that are needed only in one sex are eliminated in the opposite sex by apoptosis. In C. elegans two sets of sex-specific neurons, four cephalic companion neurons (CEMs) and two hermaphrodite specific neurons (HSNs), undergo sexually dimorphic PCDs. Although all are born embryonically in both males and hermaphrodites, the CEMs survive in males and undergo PCD in hermaphrodites. Conversely, the HSNs survive in hermaphrodites but undergo PCD in males. The sex determination pathway has been studied extensively in C. elegans but very little is known about what controls the sex-specific PCDs of these two sets of neurons. We are interested in identifying genes that operate at the intersection of the sex determination and PCD pathways. In C. elegans males the CEMs are located bilaterally between the two bulbs of the pharynx: two on the dorsal side and two on the ventral side. We have used a transgenic strain,
pha-1(
e2123ts);
him-5(
e1490); syEx313 (kindly provided by Paul Sternberg), in which GFP is specifically expressed only in the CEMs and a few tail neurons in males, to screen for mutations that cause ectopic PCD of CEMs in males or survival of CEMs in hermaphrodites. We have screened 8500 haploid genomes and have thus far isolated four mutations that affect CEMs in males and nine mutations that affect CEMs in hermaphrodites. These include (1) three mutations in two genes required for all programmed cell deaths,
ced-3(
sm120,
sm144) and
egl-1(
sm157) , (2) mutations (
sm117 and
sm150 ) in two genes that affect CEM cell fate determination, and (3) mutations (
sm119 ,
sm130, and
sm146 ) in three genes that specifically affect the life vs. death fate of the CEMs or HSNs. We have focused on studying the third class of mutants (
sm119 ,
sm130, and
sm146 ). In
sm130 mutant animals, the dorsal CEMs but not the ventral CEMs undergo ectopic PCDs in males, which can be blocked by loss-of-function mutations in
ced-3 .
sm130 is thus a dorsal CEM-specific cell death mutant. Both
sm119 and
sm146 mutations cause partial reversal of CEM/HSN cell fates: ectopic deaths of HSNs and inappropriate survival of CEMs in hermaphrodites.
sm119 and
sm146 may define genes that control the life vs. death fates of both HSNs and CEMs. We are in the process of mapping and cloning these three genes. Two mutations (
sm117 and
sm150 ) in the second class are also of interest to us. In
sm117 mutants, 100% of males lose all four CEMs. This cannot be blocked by mutations in
ced-3 , indicating that the absence of the CEMs is not due to their ectopic PCD but rather to abnormal cell fate transformation.
sm117 turns out to be an allele of
unc-86 , which has been previously implicated in the cell fate determination of the HSNs but not the CEMs.
sm150 is another interesting mutation that not only causes survival of the CEMs in 58% of the hermaphrodites but also appears to cause sister cell transformations in several other cell lineages. Specifically, in
sm150 mutants several pharyngeal cells (e.g. I2 and MC cells) undergo ectopic PCD taking on cell fates that originally belong to their sister cells. Consistent with this hypothesis, in
sm150;
ced-3 double mutants, the deaths of I2 and MC pharyngeal cells are prevented. We are in the process of mapping
sm150 . In summary, we have identified several genes that specifically affect the life vs. death fate of the CEM neurons. Further characterization of these genes should help reveal how sexually dimorphic apoptosis is regulated and executed in nematodes and may shed light on the regulation of sexual dimorphic cell deaths in general.