Programmed Neuronal Death: Genetic and Hormonal Control

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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.