Programmed Neuronal Death: Genetic and Hormonal Control

972889罗比诺神经元的选择性丧失是功能神经系统发育过程中的一个重要过程。神经系统内的细胞死亡是发育程序性的，通常通过凋亡发生，这是细胞自杀的一种内在机制，大多数(如果不是全部)细胞在发育过程中死亡。神经元死亡的程序不仅取决于神经元的特性，还取决于发育信号，如类固醇激素的滴度和营养因子的可用性。这些发育信号可能通过调节诱导或阻止特定神经元凋亡的基因的表达来发挥作用。无脊椎动物提供了一个有用的系统来研究细胞凋亡的发育调节，因为它们有相对简单的神经系统，在每个动物身上都可以可靠地重新识别单个注定要死的神经元。在果蝇黑腹果蝇中，已经确定了五个控制细胞凋亡的基因。基因“REAPER”、“GRIM”和“HID”的表达诱导细胞凋亡，而基因DIAP1和DIAP2的表达则抑制细胞凋亡。罗比诺博士将研究这五个基因在两组独立的注定要死亡的神经元中的表达。这些注定要死亡的神经元可以通过类固醇激素20-羟基蜕皮激素的治疗来预防。先前的工作表明，类固醇激素治疗阻止了一组注定要死亡的神经元中收割机基因的上调。罗比诺博士将研究类固醇激素治疗是否通过改变这些基因中其他基因的表达来防止死亡。计划进行的实验也将开始解决类固醇激素阻止死神表达的机制。该项目的结果将通过表征类固醇激素调节控制细胞凋亡的基因表达的机制，进一步加深我们对神经系统组装的理解。

972889 ROBINOW The selective loss of neurons is an important process in the development of a functional nervous system. Cell death within the nervous system is developmentally programmed and generally occurs by apoptosis, an intrinsic mechanism of cellular suicide that is employed by most, if not all, cells that die during the course of development. The programming of neuron death is conferred not only by neuronal identity, but also by developmental signals such as the titer of steroid hormones and the availability of trophic factors. These developmental signals are likely to act by regulating the expression of genes that either induce or prevent apoptosis in specific neurons. Invertebrates offer a useful system in which to investigate the developmental regulation of apoptosis, because they have relatively simple nervous systems in which individual doomed neurons can be reliably re-identified in every animal. In the fruit fly Drosophila melanogaster, five genes have been identified that control apoptosis. Expression of the genes "reaper", "grim" and "hid" induce apoptosis, whereas expression of the genes DIAP1 and DIAP2 inhibit apoptosis. Dr. Robinow will investigate the expression of these five genes in two independent sets of doomed neurons. The death of these doomed neurons can be prevented by treatment with the steroid hormone 20-hydroxyecdysone. Previous work has shown that steroid hormone treatment prevents the up-regulation of the reaper gene in one set of doomed neurons. Dr. Robinow will investigate whether steroid hormone treatment prevents death by altering the expression of others of these genes. Experiments are planned that will also begin to address the mechanism by which steroid hormone prevents reaper expression. Results from the project will further our understanding of nervous system assembly by characterizing the mechanisms by which steroid hormones act to regulate the expression of genes that control apoptosis.