Epitranscriptomic regulation in NPCs during neurodevelopment. (A) Delayed temporal progression of corticogenesis with the depletion of m⁶A RNA modification. Embryonic cortices of Mettl14 cKO mice, which have diminished m⁶A modification on mRNAs, display reduced production of deep-layer (DL) neurons and impaired production of superficial-layer (SL) neurons. During the postnatal period, Mettl14 cKO mice catch up and produce adequate numbers of deep-layer neurons but still produce fewer superficial-layer neurons. In addition, the postnatal cortices of Mettl14 cKO mice retain a residual population of RGCs similar to embryonic cortices, whereas the WT RGCs are depleted and differentiated into astrocytes after birth. These phenotypes suggest that m⁶A methylation plays a critical role in developmental fate transition of NPCs. (B) Selective facilitation of mRNA degradation by m⁶A tagging regulates mRNA turnover. Steady-state mRNA levels are determined by the rate of mRNA production and the rate of mRNA degradation. In the embryonic cortex, mRNAs without m⁶A tags including most transcripts of housekeeping genes have relatively slow turnover rates compared with m⁶A-tagged mRNAs. Meanwhile, m⁶A-tagged mRNAs, which are enriched with transcription factors (TFs) for fate-specification and cell-cycle regulators, have a faster turnover rate because of active RNA degradation. (C) A model of epitranscriptomic regulation on protein expression of transcription factors for fate specification. m⁶A mRNA modification positively regulates protein translation (by YTHDF1 and eIF3) and negatively regulates RNA stability (by YTHDF2). This dual regulation potentially enables coordinated translation and clearance of mRNA, resulting in sharp and nonoverlapping expression domains of fate-specification factors during the stepwise transition of NPCs during differentiation.