Neuronal development via redox signaling and mitochondrial dynamics

神经元网络和轴突导向是通过细胞外信号高度调节的关键过程。神经元的生长是由排斥信号分子如信号蛋白来指导的。通过氧化还原酶MICAL的活化的氧化还原反应已被证明参与脑信号蛋白介导的信号传导，然而，分子基础是未知的。我们以前已经确定了一个新的GTdR命名为CRAG，它被激活的活性氧产生的semaphorin和易位到细胞核。在本研究中，我们发现CRAG通过在核内转录调节AP-1和SRF介导神经细胞存活途径。此外，CRAG还能激活抗氧化信号，这也有助于细胞的存活.此外，我们成功地建立了CRAG条件性基因敲除小鼠。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α-Alubiquitin连接酶，通过线粒体分裂因子Drp 1的泛素化调节线粒体动力学。随后，我们提出MITOL通过泛素化未折叠蛋白如线粒体中积累的突变SOD 1和扩展polyQ参与线粒体质量控制。然而，MITOL的确切作用仍然不清楚。最近，我们确定了MITOL的两种生理底物，MAP 1B-LC 1和mitofusin 2。对MITOL的进一步分析将揭示线粒体的新作用，从而有助于更好地理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.