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Research at Mass General
The long term goal of our research is to understand the regulation and execution of apoptosis, using the powerful genetic and molecular techniques available in Drosophila. Initially, we identified several genes that act as central regulators of apoptosis. The genes: reaper, grim, hid and sickle serve as an integration point for signaling pathways that regulate developmental apoptosis, and apoptosis in response to damage. Each of these genes is responsive to a different array of upstream transcription and posttranslational regulators, and apoptosis of a particular cell is regulated by multiple upstream pathways. We are concentrating on the death of neural stem cells during development as a model for understanding how this apoptosis is specified. We have also recently focused on the developmental consequences of blocking neural stem cell death.
One strategy we have used is to screen for mutations that modify the ability of rpr, grim and hid to induce apoptosis. Among the genes we have identified with this strategy are a Drosophila homologue of the Inhibitor of Apoptosis Protein family of antiapoptotic proteins (DIAP1), and the Ras gene. We recently completed a structure/function analysis of the IAP homologue, looking at the effects of various mutations on the ability of these proteins to protect against apoptosis. Further work on Ras demonstrated that the Drosophila EGF receptor, acting through the Ras/MAPK pathway plays an important role in regulating apoptosis in the developing animal, and that the proapoptotic gene hid is an important target of EGF antiapoptotic activity.
The terminal event of apoptosis is the engulfment of cell corpses by macrophages. The Croquemort protein (CRQ), a member of the CD36 family of scavenger receptors, is expressed on macrophages in the developing Drosophila embryo. We have shown that CRQ is essential for the efficient engulfment of apoptotic cells, and have begun to explore how this protein participates in the engulfment of cell corpses, how it is regulated, and what the ligand might be on the cell corpse. We have completed a screen for mutations that show defects in engulfment of apoptotic corpses, and expect to identify many new genes important for this process.
In summary, we expect that our work will provide important insights into many aspects of apoptosis, from the initiation of the apoptotic program to the final disposal of the corpse, both in Drosophila and in mammalian systems.
Selected Publications 1. White K, Grether ME, Abrams JM, Young L, Farrell K, Steller H. GeneticControl of Programmed Cell Death in Drosophila. Science 1994; 264:677-683.
2. White K, Tahaoglu E, Steller H. Cell Killing by Drosophila reaper. Science1996; 271:805-807.
3. Kurada P, and White K. Ras promotes cell survival in Drosophila bydown-regulating hid expression. Cell 1998; 95:319-329.
4. Franc NC, Heitzler P, Ezekowitz RAB, White K. Requirement for croquemort inphagocytosis of apoptotic cells in Drosophila. Science 1999; 284:1994-1998.
5. Lisi S, Mazzon I, White K. Diverse domains of DIAP1/THREAD are required toinhibit apoptosis induced by REAPER and HID in Drosophila. Genetics2000; 154:669-678.
6. Peterson C, Carney GE, Taylor B, White K. Reaper is required forneuroblast apoptosis during Drosophila development. Development 2002;129:1467-1476.
7. Yokokura T, Dresnek, D, Huseinovic N, Lisi S, Abdelwahid E, Bangs P,White K. Dissection of DIAP1 functional domains via a mutant replacementstrategy, J Biol Chem 2004; 279:52603-52612.
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