Analysis of genes involved in cell-specific control of programmed cell death in Caenorhabditis elegans

Abstract

Programmed cell death is an important process regulating cell number in the development of all animals. Two genes, ces-1 and ces-2 control programmed cell death in a subset of developing neurons in C. elegans. To understand how ces-1 and ces-2 might act to regulate programmed cell death, we have cloned these genes. We find that both ces-1 and ces-2 encode transcription factors. By sequence and DNA-binding specificity CES-1 is a member of the Snail family of zinc-finger proteins, and most similar to the Drosophila protein Scratch. CES-2 is a bZIP protein closest in sequence and DNA-binding specificity to members of the vertebrate PAR subfamily. We have analyzed ces-1 regulation and, by conservation in the related nematode C. briggsae and by the position of the ces-1 gain-of-function mutations, identified a putative control element 5' of ces-1 coding sequences. This element contains a site that can be bound by CES-2 protein, suggesting ces-1 may be transcriptionally regulated directly by ces-2. This element also contains five Snail-like binding sites, suggesting ces-1 may regulate its own transcription. These results suggest that programmed cell death, like many cell fates, is under transcriptional control, and that a transcriptional cascade control the deaths of at least some cells in C. elegans. We propose that some of the ced genes, which are involved in the execution of programmed cell death in C.elegans, are transcriptionally regulated by CES-1 and/or CES-2. Additionally, both ces-1 and ces-2 have homologues which might function in regulating programmed cell death in mammalian cells, suggesting the functions of ces-1 and ces-2 may be evolutionarily conserved.