m6A regulation of cortical and retinal neurogenesis is mediated by the redundant m6A readers YTHDFs

m6A modification plays an important role in regulating mammalian neurogenesis. However, whether and how the major cytoplasmic m6A readers, YTHDF1, YTHDF2, and YTHDF3 mediate this process is still not clear. Here, we demonstrate that Ythdf1 and Ythdf2 double deletion but not individual knockout recapitulates the phenotype of Mettl14 knockout in cortex. In addition, we find that Mettl14 knockout in retina causes protracted proliferation of retinal progenitors, decreased numbers of retinal neurons, and disturbed laminar structure. This phenotype is only reproduced when Ythdf1, Ythdf2, and Ythdf3 are knocked out simultaneously in retina. Analysis of YTHDF target mRNAs in mouse cortex and retina reveals abundant overlapping mRNAs related to neurogenesis that are recognized and regulated by both YTHDF1 and YTHDF2. Together our results demonstrate that the functionally redundant YTHDFs mediate m6A regulation of cortical and retinal neurogenesis. [Display omitted] •YTHDF1 and YTHDF2 have redundant functions in m6A regulation of cortical neurogenesis•m6A modification plays a critical role in retinal neurogenesis•Only Ythdf1, Ythdf2, and Ythdf3 triple deletion disrupts retinal neurogenesis•YTHDF1 and YTHDF2 share a large pool of target mRNAs related to neurogenesis Molecular biology; Molecular Genetics; Neuroscience; Molecular neuroscience.