Apoptosis in Drosophila-From Reaper to Death

描述（由申请人提供）：在后生动物发育过程中，大量不需要的细胞通过细胞凋亡被清除，成体中的异常或危险细胞也是如此。正确调控的细胞凋亡对于成年人的正常发育和体内平衡是必不可少的。我们的目标是了解一个特定的细胞是如何被选择在发育的特定时间死亡的。由于广泛的信息可用于调节果蝇的其他发育决定的基因，在苍蝇的发育细胞死亡的研究有可能提供重要的洞察发育调节剂如何与凋亡机制相互作用。在目标1中，我们将确定特定的细胞群体，腹部神经母细胞或神经干细胞，是如何被告知死亡的。我们已经证明，这些细胞的死亡需要存在于Reaper基因周围的基因组区域中的遗传元件。Reaper基因是一组细胞死亡调控基因之一，包括grim，sickle和hid。我们正在解剖这个区域，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物已经被鉴定和详细研究。这些蛋白质从线虫和蝇到哺乳动物都是高度保守的。令人惊讶的是，这些蛋白质如何相互作用的机制细节似乎更加不同。根据目标2，我们建议研究线粒体在果蝇细胞凋亡中的作用。我们已经发现Reaper和Hid的表达导致线粒体透化。我们提出的策略，以确定蛋白质的重要性，这种线粒体透化，并了解其在体内细胞凋亡的作用。总之，这些研究将提供重要的见解，在发展中的动物细胞凋亡的调节和执行。

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.