N⁶-methyladenosine (m⁶A) modification of mRNA is emerging as a vital mechanism regulating RNA function. Here, we show that fragile X mental retardation protein (FMRP) reads m⁶A 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 m⁶A modification. RNA-seq and m⁶A-seq reveal that both Mettl14cKO and Fmr1KO lead to the nuclear retention of m⁶A-modified FMRP target mRNAs regulating neural differentiation, indicating that both m⁶A and FMRP are required for the nuclear export of methylated target mRNAs. FMRP preferentially binds m⁶A-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 m⁶A-dependent mRNA nuclear export during neural differentiation.

mRNA 的 N ⁶ -甲基腺苷 (m ⁶ A) 修饰正在成为调节 RNA 功能的重要机制。在这里，我们发现脆性 X 智力迟钝蛋白 (FMRP) 读取 m ⁶ A 可促进神经分化过程中甲基化 mRNA 靶标的核输出。 Fmr1敲除 (KO) 小鼠表现出神经祖细胞周期进展延迟，并且神经祖细胞增殖维持到出生后阶段，表型复制甲基转移酶Mettl14条件 KO (cKO) 小鼠没有 m ⁶ A 修饰。 RNA-seq和m ⁶ A-seq揭示Mettl14 cKO和Fmr1 KO均导致调节神经分化的m ⁶ A修饰的FMRP靶mRNA的核保留，表明m 6 A和FMRP都是m ⁶ A和FMRP的核输出所必需的。甲基化的目标 mRNA。 FMRP 优先结合 m ⁶ A 修饰的 RNA，以促进它们通过 CRM1 的核输出。核滞留缺陷可以通过野生型而非核输出缺陷型 FMRP 得到缓解，从而确立了 FMRP 在神经分化过程中介导 m ⁶ A 依赖性 mRNA 核输出中的关键作用。