In both vertebrates and invertebrates a progressive series of events culminate in the creation of the intricate pattern of neurons and their connections in the mature central nervous system (CNS). These steps include the separation of neural from epidermal precursors; the proliferation of neural precursors; and the determination (restriction of developmental potential) of group of or individual neurons. Subsequent steps include axon guidance, synaptogenesis, cell death and synaptic plasticity. Our research focuses on the processes of neural determination in Drosophila. Through a classical saturation screen we identified 204 mutations in 46 genes that control neural determination of the subset of CNS neurons that express the homeobox containing gene even-skipped (eve). We are focusing on 22 mutations in six genes, representing five novel genes and one recently identified gene (sampodo), that induce ectopic Eve-positive neurons. These mutations more likely disrupt cell fate choices than those that remove eve positive neurons, which might just block cell division. The specific aims of this proposal are: (1) to perform a detailed genetic analysis of the CNS function of sanpodo, a gene that modulates Notch signaling to specify the fate of many CNS sibling neurons; (2) to characterize at the molecular, genetic and phenotypic level the five novel genes that control neural determination; (3) to identify additional genes that control neural determination via screening large collections of extant lethal P element strains; and, (4) to improve present lineage tracing techniques to facilitate following the entire lineage of CNS neural precursors in normal and mutant backgrounds. Recent studies have found a remarkable conservation of structure, expression and function between many Drosophila genes expressed within the nervous system and their vertebrate homologs. This studies as well as initial insights from genome projects support the idea that the fundamental architecture of many biological processes are conserved between flies and humans. Thus, the identification, isolation and characterization of genes that control neural determination in Drosophila should yield general insights into the underlying molecular mechanisms that control either cell proliferation or differentiation during nervous system development. Such information may provide useful clues into the various causes of neurological or neuromuscular dysfunctions.