As a normal aspect of animal development and homeostasis, programmed cell death (apoptosis) plays an essential role in maintaining the physiological balance of appropriate cell numbers and in sculpting developing organs and tissues such as the nervous system and the sexually dimorphic reproductive systems. Abnormal activation or inactivation of apoptosis, which can lead to uncontrolled cell growth or inappropriate cell death, has been implicated in causing many human diseases such as cancer, neurodegenerative diseases, autoimmune disorders, and sexual disorders. The broad, long term objectives of this application are to understand the basic mechanisms that govern the appropriate activation of apoptosis in proper cells and to use knowledge from such studies to facilitate the understanding of human diseases caused by inappropriate apoptosis, and eventually, the development of new methods to treat and prevent apoptosis-related human diseases. Sex-specific apoptosis is an ancient developmental process that generates the appropriate sexually dimorphic reproductive structures essential for the reproduction and propagation of animal species. In the nematode C. elegans, two sets of sex-specific neurons undergo sex-specific apoptosis and thus present an ideal experimental system to study sex-specific cell death and the regulation of cell death activation. The goal of this application is to take advantage of the powerful molecular genetic techniques available in C. elegans to delineate the signaling pathways that control the execution of sexually dimorphic apoptosis and to unravel the basic molecular mechanisms that govern the activation of apoptosis. The specific aims of this application are: 1) to carry out genetic screens and analyses to identify and characterize regulators of sex-specific death (rsd genes) in C. elegans; 2) to determine the molecular identities of the identified regulators of sex-specific death; 3) to elucidate the functioning mechanisms of these regulators of sex-specific death. Given that the programmed cell death pathway is highly conserved during evolution, the studies of the regulation of sex-specific cell deaths in nematodes should provide crucial insights into the regulation of sexually dimorphic apoptosis in higher organisms, which remain poorly understood, and should contribute to the understanding of the basic mechanisms that regulate cell death activation in general.