Timing of the onset of a developmental cell death is controlled by transcriptional induction of the C. elegans ced-3 caspase-encoding gene

Temporal control of programmed cell death is necessary to ensure that cells die at only the right time during animal development. How such temporal regulation is achieved remains poorly understood. In some Caenorhabditis elegans somatic cells, transcription of the egl-1/BH3-only gene promotes cell-specific death. The EGL-1 protein inhibits the CED-9/Bcl-2 protein, resulting in the release of the caspase activator CED-4/Apaf-1. Subsequent activation of the CED-3 caspase by CED-4 leads to cell death. Despite the important role of egl-1 transcription in promoting CED-3 activity in cells destined to die, it remains unclear whether the temporal control of cell death is mediated by egl-1 expression. Here, we show that egl-1 and ced-9 play only minor roles in the death of the C. elegans tail-spike cell, demonstrating that temporal control of tail-spike cell death can be achieved in the absence of egl-1. We go on to show that the timing of the onset of tail-spike cell death is controlled by transcriptional induction of the ced-3 caspase. We characterized the developmental expression pattern of ced-3, and show that, in the tail-spike cell, ced-3 expression is induced shortly before the cell dies, and this induction is sufficient to promote the demise of the cell. Both ced-3 expression and cell death are dependent on the transcription factor PAL-1, the C. elegans homolog of the mammalian tumor suppressor gene Cdx2. PAL-1 can bind to the ced-3 promoter sites that are crucial for tail-spike cell death, suggesting that it promotes cell death by directly activating ced-3 transcription. Our results highlight a role that has not been described previously for the transcriptional regulation of caspases in controlling the timing of cell death onset during animal development.