Neuronal development via redox signaling and mitochondrial dynamics

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Neuronal network and axonal guidance are critical processes that are highly regulated through extracellular signaling. Neuronal outgrowth is directed by repelling signaling molecules such as semaphorins. Redox reaction via activation of oxidoreductase MICAL has been shown to be involved in semaphorin-mediated signaling, however, the molecular basis was unknown. We have previously identified a novel GTPase named CRAG which was activated by reactive oxygen species generated by semaphorin and translocated to the nucleus. In this study, we found that CRAG mediated neuronal cell survival pathway by transcriptional regulation of AP-1 and SRF in the nucleus. In addition, CRAG was found to activate anti-oxidant signaling which alsocontributes to the cell survival. Furthermore, we succeeded to generate CRAG conditionalknockout mice. These mice will provide an important information to understand the physiological role of CARG during neuronal development. On the other hand, MITOL is a novel mitochondrialubiquitin ligase which regulates mitochondrial dynamics by ubiquitination of mitochondrial fission factor Drp1. Subsequently, we suggested that MITOL is involved in mitochondrial quality control by ubiquitination of unfolded proteins such as mutant SOD1 and expanded polyQ accumulated in mitochondria. However, the exact role of MITOL is still obscure. Most recently we identified two physiological substrates of MITOL, MAP1B-LC1 and mitofusin2. Further analysis of MITOL will uncover the new role of mitochondria, thereby contributing to a greater understanding of the molecular basis of the neurodegenerative disorders.