During the development of multicellular animals the potentials of blast cells are progressively restricted until differentiated cell types are formed. During this process, cells decide between survival and programmed cell death. We are interested in understanding the mechanisms that control this decision and have chosen to focus on how the pattern of programmed cell deaths in the ventral cord is determined. Mutations in the Hox gene mab-5 result in survival of two cells generated in the P11 and P12 lineages of hermaphrodites that in wild type animals undergo programmed cell death. Work from the Kenyon lab had shown that MAB-5 protein is present in P11 and its descendants, but not in P12 after the first division, suggesting that mab-5 might regulate programmed cell death differently in these two lineages.We have found that in P11.aaap, but not in P12.aaap, a complex between the Hox cofactor CEH-20 and MAB-5 directly regulates transcription of the BH3 domain gene egl-1 to initiate programmed cell death. Like mab-5, ceh-20 is required for the programmed cell deaths of P11,12.aaap. Mutations of an evolutionarily conserved CEH-20/MAB-5 binding site in egl-1 result in survival of P11.aaap, but not P12.aaap. This site binds a CEH-20/MAB-5 complex in vitro. In some animals, mutation of this site results in survival of P12.pp, a cell that is not affected by ceh-20 or mab-5 mutations. Together these data suggest that the programmed cell deaths of two similar cells, P11,12.aaap, are regulated differently, and that a single site in egl-1 is used by two different complexes to activate transcription of egl-1 and programmed cell death.Two pathways have previously been described that directly regulate egl-1 transcription and programmed cell death of specific cells; these pathways include tra-1 and the ces-2 and ces-1 genes. Mammalian homologs of genes in both pathways are altered in human cancers, and, for the ces genes, regulation of programmed cell death is evolutionarily conserved and critical for oncogenesis. ceh-20 is an orthologue of Pbx1, which is frequently mutant in childhood acute lymphoblastic leukemia. These data suggest that mutations affecting Hox gene function may contribute to leukemogenesis by preventing programmed cell death.

Affiliation:
- Dept Pediatrics, Univ Texas SW Medical Ctr, Dallas, TX.