THE STUDY OF RHO FAMILY GTPase CASCADES THAT REGULATE NEURONAL MORPHOLOGY

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Rho family GTPases are known to regulate cellular motility and morphology. This study aimed at revealing the roles for Rho family GTPases in neuronal development. For this purpose, we have focused on guaninenucleotide exchange factors (GEF) that activate these GTPases. During the term of the project, we have obtained the following results.(1) We have previously identified the Drosophila still life (sif) gene by a mutant phenotype of reduced locomotor activity. This gene is predominantly expressed in the nervous system, and the protein is specifically localized at synapses. In the current project, we have revealed that the SIF protein is a GEF that activates mouse Racl in vitro and is localized in the periactive zone in the neuromuscular junction. Our genetic data indicated that SIF regulates synaptic growth. We also propose a model of synaptic structure that the periactive zone is a memebrane domain regulating synaptic development.(2) We have identified the stef gene as a mouse sif orthologue. This gene is exppressed in the migrating postmitotic cells in the cortical plate and also in the adult hypocampus, suggesting that STEF regulates neuronal motility as well as synaptic development in mouse.(3) Our finding that SIF regulating synaptic growth is localized at synaptic terminals suggests that there may be other GEFs that control distinct phenomena of neuronal development. We therefore searched GEF candidates, taking advantage of the Drosophila database. One candidate molecule, named Trio, was found to be expressed in the nervous system during the period of axonal extension. We have isolated a number of trio mutants and examined the axonal distribution patterns. Our data demonstrated that trio has a pivotal role in the regulation of axon extension.