The nucleus of the typical eukaryotic cell is located at a defined region and maintained there through active processes. Consequently changes in nuclear position are often highly regulated and play important developmental and cellular roles. Despite the ubiquity of nuclear migration, relatively little is known about the genetics and cell biology of this process in higher eukaryotes. The long-term objective of this research is to determine the mechanisms underlying nuclear migration and to understand its regulation during development, using Drosophila as a model system. Nuclear migration involves an evolutionarily conserved pathway that acts through the microtubule motor cytoplasmic dynein. The Drosophila nudC (DnudC) and Drosophila Lisl (DLisl) genes have important regulatory roles in this process and dynein is essential for movement and anchoring of the oocyte nucleus. We propose to study the mechanism by which dynein function is regulated by genes in the nuclear migration pathway using molecular and biochemical approaches. These studies will provide significant insights into how nuclear migration is regulated in a higher eukaryote and help in understanding how the activity and specificity of dynein, a key microtubule dependent motor can be modulated. Mutations in human LIS1 result in failure of neuronal migration during embryogenesis causing severe mental retardation and premature death. In addition, missense mutations in dynein motor components cause human motor neuron disease and progressive motor neuron degeneration, underscoring the clinical relevance of determining how these ubiquitous motor complexes are regulated. The three specific aims of this proposal are: 1. To investigate the role of DLisl in regulating dynein motor activity: We will examine how DLisl affects dynein function using molecular, genetic and biochemical approaches as well as a sensitive assay that directly measures motor activity in vivo. 2. To determine the biological function of DnudC: We will investigate the role of DnudC, a potential regulator of DLisl and carry out a phenotypic analysis of mutants we have isolated in DnudC. 3. To understand the mechanistic basis of DnudC function: Genetic and structure/function analysis will be used to examine regulatory interactions between DLisl/DnudC and the mechanistic basis of DnudC action. ? ? ?
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