Loss of a Hox protein complex that includes LIN-39, CEH-20 and UNC-62 results in programmed cell death of specific cells, the VC motor neurons. We sought to investigate the mechanism responsible for this context-specific pattern of cell death. Specifically, why does the VC neuron descendant of each Pn.a cell of
lin-39 mutants die, but the other five neurons generated by Pn.a survive? To address this question, we performed an RNAi screen in a
lin-39 background for repressors of programmed cell death, as visualized by a Pegl-1gfp reporter. In this strain,
egl-1 is expressed all of the cells of the ventral nerve cord that die in wild type animals and in the six VC neurons that die in
lin-39 mutants, but not in any other P cell descendants. From this screen, we identified the gene F49E12.6. In
lin-39; F49E12.6(RNAi) animals,
egl-1 is expressed in the VA and VB motor neurons, in addition to the VC neurons. Remarkably, repression of
egl-1 by F49E12.6 is redundant with
lin-39. In F49E12.6(RNAi) animals,
egl-1 is expressed in the VA and VB neurons in the posterior P cell lineages outside the midbody region in which
lin-39 is normally active;
egl-1 is not expressed in the midbody, where
lin-39 is active. These data suggest that F49E12.6 and LIN-39 act redundantly to repress transcription of
egl-1 in the VA and VB motor neurons of the midbody, and may in part explain the context-dependent requirement for
lin-39 function in ensuring VC neuron survival. F49E12.6 encodes a C. elegans homolog of the mammalian transcription factors E2F7 and E2F8. E2F7 and E2F8 are recently discovered proteins that are unique in having two E2F DNA-binding domains and in lacking domains present in other E2F family members, such as DP/DPL-1-binding or Rb/LIN-35 binding domains. Mice with knockouts of E2f7 or E2f8 are viable, but the double mutant is lethal with widespread apoptosis. The precise mechanisms through which loss of E2f7 and E2f8 result in apoptosis are as yet unclear, and our data suggest transcriptional derepression of programmed cell death pathway genes in the double mutants, perhaps in a context-dependent manner involving Hox genes, is one such mechanism.