The long-term goals of this proposal are to understand the mechanisms that allow cytoplasmic dynein to perform diverse, yet independently controlled functions in neurons, including retrograde and slow anterograde axonal transport, and to understand the significance of dynein-dependent neuronal nuclear migration during development. Functional specificity of cytoplasmic dynein has been attributed to variation in subunit composition of motor complexes and to accessory polypeptides that recruit the motor to certain transport tasks. This proposal tests this hypothesis using the powerful molecular biology, genetics and transgenic techniques of Drosophila. Specifically, the proposed experiments assess the functional specificity of various isoforms of the dynein intermediate chain by analyzing their subcellular localization, as well as determining whether animals that lack specific isoforms exhibit defects in neuronal function and development. To define which other molecules might contribute to dynein specificity in neurons, experiments are proposed to compare the effect of a collection of mutants implicated in dynein function on neuron-specific transport processes. An important role of dynein-based transport is positioning and organizing subcellular components, including nuclei. The nuclei of the photoreceptors of the Drosophila eye undergo stereotypic, dynein-dependent nuclear migrations that culminate in specific nuclear positioning for each class of photoreceptor. The biological significance of the precise nuclear positioning is unknown. The emergent microarray technology will be utilized to profile differences in transcription on a genome-wide basis in eyes with normally localized and with mispositioned nuclei. The extensive knowledge about the interplay between signal transduction and gene expression in the Drosophila eye will facilitate analyzing any observed differences. Aberrant motor function has been linked to anomalous brain development and neurological and neurodegenerative diseases, including Miller-Dieker lissencephaly, schizophrenia, Charcot-Marie-Tooth Disease Type 2A, human motor neuron disease, retinitis pigmentosa, and Alzheimer's disease.
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