Neuronal development via redox signaling and mitochondrial dynamics

神经网络和轴突引导是细胞外信号高度调控的关键过程。神经元的生长是由排斥信号分子（如信号素）引导的。氧化还原酶micical激活的氧化还原反应已被证明参与信号素介导的信号传导，然而，其分子基础尚不清楚。我们之前已经发现了一种名为CRAG的新型GTPase，它被信号蛋白产生的活性氧激活并转移到细胞核中。本研究发现CRAG通过细胞核内AP-1和SRF的转录调控介导神经元细胞存活通路。此外，CRAG还被发现激活抗氧化信号，这也有助于细胞存活。此外，我们成功地产生了CRAG条件敲除小鼠。这些小鼠将为了解CARG在神经元发育过程中的生理作用提供重要信息。另一方面，MITOL是一种新的线粒体泛素连接酶，它通过线粒体裂变因子Drp1的泛素化来调节线粒体动力学。随后，我们提出MITOL参与线粒体质量控制，通过泛素化未折叠蛋白，如突变体SOD1和线粒体中积累的扩增polyQ。然而，MITOL的确切作用仍然不清楚。最近，我们确定了MITOL的两个生理底物，MAP1B-LC1和mitofusin2。对MITOL的进一步分析将揭示线粒体的新作用，从而有助于更好地了解神经退行性疾病的分子基础。

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.