The long-term goal of the research is to understand the molecular mechanism by which neurons acquire their characteristic pattern of connectivity during development. Recent evidence suggests that Rac and Cdc42, members of small GTPase of the Rho subfamily, mediate signaling from extracellular factors to the actin cytoskeleton in the regulation of neuronal arborization. The PI identified a Cdc42-binding protein, C17, in Drosophila. C17 binds to Cdc42 in a GTP-dependent manner and is highly enriched in the nervous system at the time of axonal and dendritic outgrowth. The amino third of C17 shares homology with human myotonic dystrophy protein kinase. In addition, C17 also contains domains suggestive of cytoskeletal association and regulation by other signaling molecules. The c17 mutants display defects in actin cytoskeleton and neuronal function. In this proposal, the role of C17 in the morphogenesis of neurons will be assessed by genetic interaction with other genes required in axon guidance, by biochemical studies of the regulation of its kinase activity, and by subcellular localization studies. In addition, the function of mouse C17 homolog in the morphogenesis of cerebellar Purkinje cells will be analyzed by expressing dominant negative mutants of mouse C17. Knowledge of how neurons generate axons and dendrites in development may help us understand regeneration following nerve injury. The high degree of sequence similarity between C17 and myotonic dystrophy protein kinase suggests functional similarities of the two proteins. Thus understanding the biological function C17 may shed light on the molecular pathogenesis of myotonic dystrophy, the most common adult form of muscular dystrophy.
Showing the most recent 10 out of 11 publications
