Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Biochemistry, Molecular and Cellular Biology Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell Rep. 2019 Jul 23;28(4):845-854.e5. doi: 10.1016/j.celrep.2019.06.072.
N-methyladenosine (mA) modification of mRNA is emerging as a vital mechanism regulating RNA function. Here, we show that fragile X mental retardation protein (FMRP) reads mA to promote nuclear export of methylated mRNA targets during neural differentiation. Fmr1 knockout (KO) mice show delayed neural progenitor cell cycle progression and extended maintenance of proliferating neural progenitors into postnatal stages, phenocopying methyltransferase Mettl14 conditional KO (cKO) mice that have no mA modification. RNA-seq and mA-seq reveal that both Mettl14cKO and Fmr1KO lead to the nuclear retention of mA-modified FMRP target mRNAs regulating neural differentiation, indicating that both mA and FMRP are required for the nuclear export of methylated target mRNAs. FMRP preferentially binds mA-modified RNAs to facilitate their nuclear export through CRM1. The nuclear retention defect can be mitigated by wild-type but not nuclear export-deficient FMRP, establishing a critical role for FMRP in mediating mA-dependent mRNA nuclear export during neural differentiation.
N6-甲基腺苷（m6A）修饰的 mRNA 作为一种重要的调控 RNA 功能的机制正在出现。在这里，我们表明脆性 X 智力低下蛋白（FMRP）读取 m6A 以促进神经分化过程中甲基化 mRNA 靶标的核输出。Fmr1 敲除（KO）小鼠显示出神经前体细胞周期进展延迟，以及增殖性神经前体细胞在出生后阶段的维持延长，这与没有 m6A 修饰的甲基转移酶 Mettl14 条件性 KO（cKO）小鼠的表型相同。RNA-seq 和 m6A-seq 表明，Mettl14cKO 和 Fmr1KO 都导致调节神经分化的 m6A 修饰的 FMRP 靶 mRNA 的核保留，表明 m6A 和 FMRP 均是甲基化靶 mRNA 核输出所必需的。FMRP 优先结合 m6A 修饰的 RNA，通过 CRM1 促进其核输出。野生型而非核输出缺陷型 FMRP 可减轻核保留缺陷，这确立了 FMRP 在介导神经分化过程中 m6A 依赖性 mRNA 核输出中的关键作用。
