Apoptosis in Drosophila-From Reaper to Death

描述(由申请人提供)：在后生动物的发育过程中，大量不需要的细胞通过细胞凋亡被消除，成人的异常或危险细胞也是如此。正确调控细胞凋亡对于成人的正常发育和动态平衡是必不可少的。我们的目标是了解特定的细胞是如何被选择在发育的特定时间死亡的。由于有关调控果蝇其他发育决定的基因的广泛信息，对果蝇发育细胞死亡的研究有可能为了解发育调节因子如何与细胞凋亡机制相互作用提供重要的见解。在目标1中，我们将确定一组特定的细胞，即腹部神经母细胞或神经干细胞，是如何发出死亡信号的。我们已经证明，这些细胞的死亡需要存在于收割者基因周围的基因组区域的遗传元件。收割者基因是一系列细胞死亡调控基因之一，包括GRIM、FIFLE和HID。我们正在解剖这一区域，以了解细胞死亡基因的表达是如何协调调节的。许多细胞凋亡的分子效应因子已经被识别和详细研究。这些蛋白质从线虫和苍蝇到哺乳动物都是高度保守的。令人惊讶的是，这些蛋白质相互作用的机制细节似乎更加不同。在目标2下，我们建议研究线粒体在果蝇细胞凋亡中的作用。我们发现Reaper和HID的表达导致了线粒体的通透性。我们提出了识别这种线粒体通透性的重要蛋白质的策略，并了解其在体内细胞凋亡中的作用。综上所述，这些研究将为在发育中的动物中调节和执行细胞凋亡提供重要的见解。

DESCRIPTION (provided by applicant): During metazoan development, large numbers of unwanted cells are eliminated by apoptosis, as are abnormal or dangerous cells in the adult. Correctly regulated apoptosis is essential for normal development and homeostasis of the adult. Our goal is to understand how a particular cell is selected to die at a particular time in development. Because of the extensive information available about the genes that regulate other developmental decisions in Drosophila, the study of developmental cell death in flies has the potential to provide important insight into how developmental regulators interact with the apoptotic machinery. Under aim 1, we will determine how a specific population of cells, the abdominal neuroblasts, or neural stem cells, are signaled to die. We have shown that the death of these cells requires genetic elements present in the genomic region around the Reaper gene. The Reaper gene is one of a cluster of cell death regulatory genes including grim, sickle and hid. We are dissecting this region in order to understand how the expression of cell death genes is coordinately regulated. Many of the molecular effectors of apoptosis have been identified and studied in great detail. These proteins are highly conserved from nematodes and flies through mammals. Surprisingly, the mechanistic details of how these proteins interact appear more divergent. Under aim 2, we propose to examine the role of the mitochondria in Drosophila apoptosis. We have found that expression of Reaper and Hid result in mitochondrial permeabilization. We propose strategies to identify proteins important for this mitochondrial permeabilization, and to understand its role in apoptosis in vivo. Taken together, these studies will provide important insight into the regulation and execution of apoptosis in the developing animal.