We are working to define the genetic pathways that determine the pattern of programmed cell deaths in a single tissue of C. elegans, the ventral nerve cord. We identified two recessive mutations,
n3168 and
n3192 that resulted in up to six cell corpses in the midregion of the ventral nerve cord, where no cells undergo programmed cell death in wild type animals, and a reduced number of cell corpses in the posterior ventral nerve cord.
n3168 mutants lacked VC motor neuron nuclei when assayed using a Plin-11gfp reporter that is expressed in the VC motor neurons. In double mutants with the
n3168 mutation and a loss of function mutation in
egl-1 the VC motor neurons survived, suggesting that the gene defined by
n3168 functions upstream or parallel to the programmed cell death pathway. We mapped
n3168 and
n3192 to a small region on LGI near the Trithorax group gene
lin-59. RNAi of the
lin-59 gene phenocopied the defects in programmed cell deaths we observed in
n3168 and
n3192 mutants, suggesting that these mutations affect
lin-59. We confirmed this by identifying premature stop mutations in the genomic sequence of
lin-59 in
n3168 and
n3192 mutants. Genetic analyses suggested that
n3168 and
n3192 are not null alleles. A null allele we identified in a deletion library is a larval lethal mutation. Helen Chamberlin identified mutations in
lin-59 in a screen for mutants with abnormal male tails, and suggested that
lin-59 maintained expression of HOM-C genes, consistent with the role of the Trithorax group genes in Drosophila. In C. elegans, the HOM-C gene
lin-39 is essential for survival of the VC motor neurons, and
mab-5 is essential for the programmed cell deaths of P11,12.aaap. Consistent with the hypothesis that reduced
lin-39 and
mab-5 function may mediate the abnormalities in programmed cell death in
lin-59 mutants, we followed cell lineages in
lin-59(
n3168) mutants and find that the VC motor neurons can undergo programmed cell death, and P11/12.aaap can survive. Semiquantitative RT PCR of total mRNA isolated from
lin-59(
n3168) mutants indicates that
lin-39 and
mab-5 transcripts are markedly reduced. In Drosophila, the
lin-59 homologue Ash1 is required for the function of Trithorax. Mutations affect the mammalian homologue of Trithorax, MLL, in more than 70 percent of infants with leukemia. We suggest that a mechanistic understanding of how
lin-59 prevents programmed cell death of the VC motor neurons will be relevant to how MLL contributes to leukemogenesis.