FMRP Modulates Neural Differentiation through m⁶A-Dependent mRNA Nuclear Export

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.