| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Formation and extension of axons and dendrites, so-called neurite outgrowth, is a crucial event in neuronal differentiation and maturation during development of the nervous system. These morphological changes require reorganization of the cytoskeletal networks and its accompanying membrane expansion and contraction. Rap1 small G protein has been shown to be involved in neurite outgrowth and neuronal polarization through regulating the MAP kinase (MAPK) cascade and the cytoskeletal network. Rho small G protein has been shown to be involved in the morphological development of neurons through regulating actin dynamics. We previously showed that inactivation of Rho is required for the Induced-induced neurite outgrowth. Activated-activated Rho GTPase-activating protein, RA-RhoGAP, transduces a signal from Rap1 to Rho and inactivates Rho. The precise temporary and spatially activation of Rap1 is important for regulating the activity of RA-RhoGAP to produce the neurite. However, the mechanism underlying how and where Rap1 is activated remains unclear. In the present research project, we identified that a GDP/GTP exchange factor (GEF) for Rap1,PDZ-GEF1,was implicated in these events.
1) PDZ-GEF1 was activated by GTP-Rap1 in a feedback mechanism.
2) In PC12 cells, transport of nerve growth factor (NGF)-bound TrkA receptor to late endosomes is required for the NGF-induced sustained activation of Rap1.
3) In PC12 cells, ARMS bound S-SCAM, which formed a complex with PDZ-GEF1, and recruited the complex to late endosomes. This tetramer complex at late endosomes induced sustained activation of Rap1 and ERK, resulting in neurite outgrowth.
4) In cultured rat hippocampal neurons, the PDZ-GEF1 tetramer complex on late endosomes is involved in the axon specification and elongation.
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