A circular RNA Edis-Relish-castor axis regulates neuronal development in Drosophila.
A circular RNA Edis-Relish-castor axis regulates neuronal development in Drosophila.
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DOI：
10.1371/journal.pgen.1010433
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发表时间：
2022-10
期刊：
影响因子：
4.5
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Circular RNA（circRNA）是一类新的非编码/调节RNA，在神经系统中含量特别丰富，但其生理功能尚不清楚。在这里，我们报告说，脑富集的环状RNA Edis（Ect 4衍生的免疫抑制剂）在果蝇神经元发育中起着至关重要的作用。我们发现，Edis在体内的耗尽导致缺陷的轴突投射模式的蘑菇体（MB）神经元在大脑中，以及受损的运动活动和寿命缩短的成年苍蝇。此外，我们发现蓖麻基因，它编码的转录因子参与神经发育，上调Edis敲低神经元。值得注意的是，蓖麻过度表达表型模仿Edis敲低，并且降低蓖麻水平抑制Edis耗尽的神经元中的神经发育表型。此外，染色质免疫沉淀分析表明，转录因子Relish，它在调节先天免疫信号传导中起着关键作用，占据了蓖麻启动子上的一对位点，并且这两个位点都是通过免疫挑战或Edis耗竭来最佳激活蓖麻基因所需的。最后，Relish突变和/或缺失可以挽救蓖麻基因过度活化表型和Edis敲低动物中的神经元缺陷。我们的结论是，环状RNA Edis通过Relish和蓖麻来调节神经元的发育。Circular RNA（circRNA）是一类新的非编码/调节RNA，在神经系统中特别丰富，但其生理功能尚未完全阐明。在这里，我们报告说，大脑富集的环状RNA Edis（Ect 4衍生的免疫抑制剂）在果蝇的神经元发育中起着至关重要的作用，因为它的耗尽会导致称为蘑菇体（MB）的大脑结构中神经元发育的缺陷，以及成年果蝇的运动活动受损和寿命缩短。此外，我们表明，蓖麻基因，它编码的蛋白质参与神经发育，上调Edis敲低神经元。值得注意的是，蓖麻水平升高或Edis水平降低的果蝇表现出相似的表型，并且降低蓖麻水平可以挽救Edis缺失神经元的发育缺陷。此外，我们发现，免疫调节剂美味占据了一对网站在蓖麻基因位点，这两个网站所需的最佳蓖麻基因激活无论是免疫挑战或Edis耗尽。最后，Relish突变和/或缺失可以挽救蓖麻基因过度活化表型和Edis敲低动物中的神经元缺陷。我们的结论是，环状RNA Edis通过Relish和蓖麻来调节神经元的发育。
Circular RNAs (circRNAs) are a new group of noncoding/regulatory RNAs that are particularly abundant in the nervous system, however, their physiological functions are underexplored. Here we report that the brain-enriched circular RNA Edis (Ect4-derived immune suppressor) plays an essential role in neuronal development in Drosophila. We show that depletion of Edis in vivo causes defects in axonal projection patterns of mushroom body (MB) neurons in the brain, as well as impaired locomotor activity and shortened lifespan of adult flies. In addition, we find that the castor gene, which encodes a transcription factor involved in neurodevelopment, is upregulated in Edis knockdown neurons. Notably, castor overexpression phenocopies Edis knockdown, and reducing castor levels suppresses the neurodevelopmental phenotypes in Edis-depleted neurons. Furthermore, chromatin immunoprecipitation analysis reveals that the transcription factor Relish, which plays a key role in regulating innate immunity signaling, occupies a pair of sites at the castor promoter, and that both sites are required for optimal castor gene activation by either immune challenge or Edis depletion. Lastly, Relish mutation and/or depletion can rescue both the castor gene hyperactivation phenotype and neuronal defects in Edis knockdown animals. We conclude that the circular RNA Edis acts through Relish and castor to regulate neuronal development. Circular RNAs (circRNAs) are a new group of noncoding/regulatory RNAs that are particularly abundant in the nervous system, although their physiological functions are underexplored. Here we report that the brain-enriched circular RNA Edis (Ect4-derived immune suppressor) plays an essential role in neuronal development in the fruitfly Drosophila melanogaster, as its depletion causes defects in the development of neurons in a brain structure called mushroom body (MB), as well as impaired locomotor activity and shortened lifespan of adult flies. In addition, we show that the castor gene, which encodes a protein involved in neurodevelopment, is upregulated in Edis knockdown neurons. Notably, flies with increased levels of castor or reduced levels of Edis display similar phenotypes, and reducing castor levels rescues the developmental defects in Edis-depleted neurons. Furthermore, we find that the immune regulator Relish occupies a pair of sites at the castor gene locus, and that both sites are required for optimal castor gene activation by either immune challenge or Edis depletion. Lastly, Relish mutation and/or depletion can rescue both the castor gene hyperactivation phenotype and neuronal defects in Edis knockdown animals. We conclude that the circular RNA Edis acts through Relish and castor to regulate neuronal development.
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