C3orf70 Is Involved in Neural and Neurobehavioral Development
C3orf70 Is Involved in Neural and Neurobehavioral Development
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DOI：
10.3390/ph12040156
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发表时间：
2019-12-01
期刊：
影响因子：
4.6
通讯作者：
Nishimura, Yuhei
中科院分区：
文献类型：
--
作者：
Ashikawa, Yoshifumi;Shiromizu, Takashi;Nishimura, Yuhei
神经发生是未分化的祖细胞发育成成熟和功能性神经元的过程。神经发生的缺陷与神经发育和神经精神疾病有关;因此，阐明神经发生的分子机制可以促进我们对这些疾病的病理生理学的理解，并有助于发现新的治疗靶点。在这项研究中，我们进行了比较转录组学分析，以确定共同的目标前神经转录因子Neurog 1/2和Ascl 1在人类和小鼠干细胞的神经发生。我们成功地确定了C3 orf 70作为神经发生过程中Neurog 1/2和Ascl 1的一个新的共同靶基因。利用原位杂交技术，我们证明了C3 orf 70的两个同源基因c3 orf 70 a和c3 orf 70 b在斑马鱼幼鱼的中脑和后脑中表达。我们使用CRISPR/Cas9技术产生了c3 orf 70敲除斑马鱼，并证明c3 orf 70的缺失导致成熟神经元标记物elavl 3和eno 2的表达显着降低。我们还发现，在c3 orf 70敲除斑马鱼中，IRX 3的斑马鱼直系同源物和中脑/后脑标记物irx 3b的表达显著降低。最后，我们证明了在c3 orf 70基因敲除的斑马鱼中，与昼夜节律和改变的明暗条件相关的神经行为显著受损。这些结果表明，C3 orf 70参与神经和神经行为发育，C3 orf 70的缺陷可能与中脑/后脑相关的神经发育和神经精神疾病。
Neurogenesis is the process by which undifferentiated progenitor cells develop into mature and functional neurons. Defects in neurogenesis are associated with neurodevelopmental and neuropsychiatric disorders; therefore, elucidating the molecular mechanisms underlying neurogenesis can advance our understanding of the pathophysiology of these disorders and facilitate the discovery of novel therapeutic targets. In this study, we performed a comparative transcriptomic analysis to identify common targets of the proneural transcription factors Neurog1/2 and Ascl1 during neurogenesis of human and mouse stem cells. We successfully identified C3orf70 as a novel common target gene of Neurog1/2 and Ascl1 during neurogenesis. Using in situ hybridization, we demonstrated that c3orf70a and c3orf70b, two orthologs of C3orf70, were expressed in the midbrain and hindbrain of zebrafish larvae. We generated c3orf70 knockout zebrafish using CRISPR/Cas9 technology and demonstrated that loss of c3orf70 resulted in significantly decreased expression of the mature neuron markers elavl3 and eno2. We also found that expression of irx3b, a zebrafish ortholog of IRX3 and a midbrain/hindbrain marker, was significantly reduced in c3orf70 knockout zebrafish. Finally, we demonstrated that neurobehaviors related to circadian rhythm and altered light-dark conditions were significantly impaired in c3orf70 knockout zebrafish. These results suggest that C3orf70 is involved in neural and neurobehavioral development and that defects in C3orf70 may be associated with midbrain/hindbrain-related neurodevelopmental and neuropsychiatric disorders.