MYOSIN V FUNCTION IN THE NERVOUS SYSTEM

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DESCRIPTION (adapted from applicant's abstract): Dilute-lethal mice (i.e., myosin V null mutants) exhibit ataxia, convulsion with clonic link movements, and opisthotonus suggesting that they have defects in central nervous system. function. Death occurs at about 3 weeks of age. a certain rare human genetic disease (Griscelli disease) has been identified which results from mutations in the myosin V gene, and similar to the mouse mutation, can be lethal. 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. Recent morphological data has also identified a specific defect in smooth endoplasmic reticulum localization in cerebellar Purkinje cells of dilute-lethal mice. There is additional evidence that myosin V associates with synaptic vesicles and may contribute to regulate the transport of these organelles or their precursors along actin filaments. Furthermore, myosin V may associate with a complex of proteins responsible for the anchoring of NMDA type glutamate receptors. Taken together these results suggest that the neurological defects in dilute-lethal mice (and humans) may result from a combination of impaired organelle trafficking and protein localization in neurons. Because of the organelles and proteins involved, this could have profound effects on synaptic efficacy. Thus, this system allows the applicants to address both the molecular mechanism of myosin V function and the important consequences of its activity for the nervous system at both cellular and behavioral levels. The applicant's current goals are to: (1) determine the consequences of the dilute-lethal structural defects for synaptic physiology at the synapse between granule cells and Purkinje cells, (2) determine the mechanism through which myosin V targets smooth endoplasmic reticulum to dendritic spines, (3) determine the consequences of myosin V's absence on the localization of NMDA receptors and associate postsynaptic proteins, and (4) determine if presynaptic terminals of dilute-lethal granule cells have abnormal organelle transport of processing. To accomplish these goals, a combination of electrophysiological, live imaging and morphological techniques will be used.