Programmed cell death (PCD) is important for animal development and understanding this process may provide insight into human ailments such as cancer and neurodegenerative disease. Although much is known about global control of apoptotic cell death, relatively little is known about cell-specific signals that regulate PCD during development. Our long term goals are to understand the molecular features that distinguish cells destined to live from those destined to die; to understand how temporal control of cell death is achieved; and to determine whether caspase-dependent cell death is the only mode of cell death used during animal development. C. elegans is an excellent organism in which to study the control of PCD. Dying cells in developing animals are easily visualized, and genetic and molecular studies of PCD genes are generally facile. Most PCD in C. elegans is regulated by an evolutionarily conserved molecular pathway. Specifically, CED-3/caspase promotes PCD following activation by CED-4/Apaf-1. This process is kept in check by CED-9/Bcl-2, which inhibits CED-4, and by EGL-1, a BH3 domain-containing inhibitor of CED-9. It is widely believed that control of cell-specific death and its onset are regulated by controlling EGL-1 activity. However, we demonstrated two instances in which this paradigm does not hold up. First, in the tail-spike cell, CED-9 and EGL-1 play only a minor role in the control of cell death. In this cell, onset of death appears to be controlled by transcriptional induction of the ced-3 gene using the PAL-1 transcription factor, the C. elegans homolog of the vertebrate tumor-suppressor gene Cdx2. Second, in the linker cell, a program independent of all known cell death genes previously described in C. elegans, regulates cell death. Remarkably, this non-apoptotic program is morphologically similar to forms of vertebrate cell death that have not been studied in detail, suggesting that the process is likely to be conserved. Here we plan to pursue two specific aims: (1) We will use genetic and molecular approaches to understand how ced-3 transcription is controlled in the tail-spike cell to promote cell death. (2) We will use genetic strategies to uncover the mechanism by which the novel cell death pathway we discovered executes linker cell death. Given the morphological and molecular similarities between cell death programs in C. elegans and vertebrates, our studies are likely to reveal basic principles of cell death regulation common to these organisms. Public health: Inappropriate cell death underlies a host of human illnesses including neurodegenerative diseases, and lack of cell death is a major contributor to tumor development. Our studies will shed light on basic mechanisms regulating cell death, and should define proteins that may be used as therapeutic targets. ? ? ?
