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Genes and Networks that Support Apoptosis

Like mammalian counterparts, the Drosophila apoptosome, occupies a centralposition in networks that specify PCD. To advance a comprehensive view of pivotal cell death regulators and discover novel apoptogenic functions, we are pursuing unbiased genetic approaches.  

Screens for PCD genes in vivo

We showed that lesions in canonical apoptotic pathways cause wing epithelial cells, normally fated for death after eclosion, to persist thereby prompting a uniquely characteristic, late-onset phenotype.  Therefore, novel PCD genes, if similarly eliminated in the wing, should also phenocopy these distinctive defects.  Based on this rationale, we are conducting a large scale screening effort and have already recovered several promising mutants. Some of these encode essential apoptotic determinants in distinct tissue types.

High throughput gene silencing platforms

Recent developments in RNAi technology, combined with high throughput cell-based assay systems, enable methodical testing of annotated genes for functional properties at the genome scale. Compared to mammalian cell systems, genome-scale screens in Drosophila culture systems offer decisive advantages. First, with fewer input and endpoint components in many pathways, reduced signaling complexity inherently minimizes confounding effects associated with network redundancy. Second, high efficiency dsRNA delivery is easily achieved without transfection. This avoids confounding effects associated with transfection stress and considerably simplifies screening logistics and data interpretation. A third key advantage draws upon attractive prospects for extending discoveries in cell-based assays to sophisticated whole animal models. We are exploiting cell-based RNAi screening platforms to capture novel effectors of apoptotic cell death using stimuli that simulate programmed signals (e.g. Reaper proteins) or injury associated stress.