Serotonin is a conserved neurotransmitter in both invertebrates and vertebrates, It has important roles in locomotion, learning and memory and is an important pharmacological target in the treatment of psychiatric and neurological disorders. This proposal examines the molecular mechanisms that underlie the development of serotonin neurons in Drosophila. Identification of genes and signaling pathways that determine the unique identity of serotonin neurons will make it possible to genetically manipulate serotonin levels and study how this affects neurogenesis, serotonin receptor distribution and fly behavior. Mechanisms of differentiation are well conserved between Drosophila and vertebrates, so our understanding of what components are necessary for serotonin cell development in Drosophila could contribute to the development of new diagnostic tests or therapeutic treatments for diseases that affect serotonin neurotransmission. The specific aims of this application are designed to investigate the interaction of two signaling pathways in the development of serotonin neurons. Our preliminary data supports a hypothesis that Notch-mediated cell-cell signaling induces apoptosis within the serotonin lineage. This Notch-induced apoptosis must be inactivated for normal development of serotonin neurons. We have evidence that the membrane-associate protein Numb can inactivate Notch signaling and prevent apoptosis. In other cell lineages the Ras signaling pathway has been implicated in inhibiting apoptosis. This proposal investigates the role of both these signal transduction pathways in the development of serotonin neurons. The specific aims of this proposal will be accomplished using a combination of molecular genetics, immunohistochemistry and confocal microscopy.