MYOSIN V FUNCTION IN THE NERVOUS SYSTEM

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Dilute-lethal mice (i.e., myosin V null mutants) exhibit ataxia, convulsions with clonic limb movements, and opisthotonus suggesting that they have defects in central-nervous system function. Death occurs at about 3 weeks of age. Thus, they may represent a good model system for studying neurodegenerative disease associated with early onset, progressive epilepsies. The dilute mouse model is particularly attractive because of the distinct phenotype exhibited by the myosin V null mutants, combined with the fact that it is one of few mutations in which the gene product has been identified and the function of the protein extensively studied. Furthermore, certain rare human genetic diseases have been identified which have similar characteristics to the dilute mouse mutation. However, because myosin V is expressed in both neuronal and nonneuronal tissues the primary defect causing abnormal neurologic symptoms may or may not reside in nervous tissue. Thus, the first goal is to determine the cellular site(s) that cause the neurologic abnormalities in dilute-lethal mice. This will be accomplished through the use of a combination of biochemical, molecular biological, and morphological approaches that include immunoblots, Northern blots, cell culture and electron microscopy of dilute-lethal and wild-type mouse tissues. There is evidence that myosin V may participate in organelle transport along actin filaments. This suggests that the neurological defects in dilute-lethal mice may result from impaired organelle trafficking in neurons. The next goal will be to establish whether organelles associate with myosin V. The final goal will be to determine if myosin V is required for organelle movement on actin filaments. These goals will be accomplished through the use of correlative light/electron microscopy, subcellular fractionation, and an in vitro motility assay. These experiments will allow comparison between abnormal neurologic symptoms in mice, and altered molecular/cellular function of a specific protein myosin V. These studies are likely to contribute to a more complete understanding of nerve cell function, and the specific aberrations that cause neurologic abnormalities in mice and humans.