Center for Integrative Genomics, Génopode Building, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
EMBO J. 2021 Feb 15;40(4):e104975. doi: 10.15252/embj.2020104975. Epub 2021 Jan 11.
N6-methyladenosine (m A) regulates a variety of physiological processes through modulation of RNA metabolism. This modification is particularly enriched in the nervous system of several species, and its dysregulation has been associated with neurodevelopmental defects and neural dysfunctions. In Drosophila, loss of m A alters fly behavior, albeit the underlying molecular mechanism and the role of m A during nervous system development have remained elusive. Here we find that impairment of the m A pathway leads to axonal overgrowth and misguidance at larval neuromuscular junctions as well as in the adult mushroom bodies. We identify Ythdf as the main m A reader in the nervous system, being required to limit axonal growth. Mechanistically, we show that the m A reader Ythdf directly interacts with Fmr1, the fly homolog of Fragile X mental retardation RNA binding protein (FMRP), to inhibit the translation of key transcripts involved in axonal growth regulation. Altogether, this study demonstrates that the m A pathway controls development of the nervous system and modulates Fmr1 target transcript selection.
N6-甲基腺苷（m A）通过调节 RNA 代谢来调节多种生理过程。这种修饰在几种物种的神经系统中特别丰富，其失调与神经发育缺陷和神经功能障碍有关。在果蝇中，m A 的缺失改变了果蝇的行为，尽管其潜在的分子机制和 m A 在神经系统发育过程中的作用仍然难以捉摸。在这里，我们发现 m A 途径的损伤会导致幼虫神经肌肉连接处以及成年蘑菇体的轴突过度生长和误导。我们确定 Ythdf 是神经系统中主要的 m A 阅读器，需要限制轴突生长。在机制上，我们表明，m A 阅读器 Ythdf 直接与 Fmr1 相互作用，Fmr1 是脆性 X 智力迟钝 RNA 结合蛋白（FMRP）的果蝇同源物，以抑制参与轴突生长调节的关键转录物的翻译。总的来说，这项研究表明，m A 途径控制神经系统的发育，并调节 Fmr1 靶转录本的选择。
