Ythdf2-mediated mA mRNA clearance modulates neural development in mice.

Background: N -methyladenosine (mA) modification in mRNAs was recently shown to be dynamically regulated, indicating a pivotal role in multiple developmental processes. Most recently, it was shown that the Mettl3-Mettl14 writer complex of this mark is required for the temporal control of cortical neurogenesis. The mA reader protein Ythdf2 promotes mRNA degradation by recognizing mA and recruiting the mRNA decay machinery.

Results: We show that the conditional depletion of the mA reader protein Ythdf2 in mice causes lethality at late embryonic developmental stages, with embryos characterized by compromised neural development. We demonstrate that neural stem/progenitor cell (NSPC) self-renewal and spatiotemporal generation of neurons and other cell types are severely impacted by the loss of Ythdf2 in embryonic neocortex. Combining in vivo and in vitro assays, we show that the proliferation and differentiation capabilities of NSPCs decrease significantly in Ythdf2 embryos. The Ythdf2 neurons are unable to produce normally functioning neurites, leading to failure in recovery upon reactive oxygen species stimulation. Consistently, expression of genes enriched in neural development pathways is significantly disturbed. Detailed analysis of the mA-methylomes of Ythdf2 NSPCs identifies that the JAK-STAT cascade inhibitory genes contribute to neuroprotection and neurite outgrowths show increased expression and mA enrichment. In agreement with the function of Ythdf2, delayed degradation of neuron differentiation-related mA-containing mRNAs is seen in Ythdf2 NSPCs.

Conclusions: We show that the mA reader protein Ythdf2 modulates neural development by promoting mA-dependent degradation of neural development-related mRNA targets.