Converged Epitranscriptomic Co-regulation of TGFβ Signaling Components Suppresses the Quiescence Transition of Early Postnatal Hippocampal Neural Stem Cells

Quiescence acquisition of proliferating neural stem cells (NSCs) is required to establish the adult NSC pool yet the underlying molecular mechanisms are not well-understood. Here we showed that conditional deletion of the m6A reader Ythdf2, which promotes mRNA decay, in proliferating NSCs in the early postnatal mouse hippocampus led to elevated quiescence acquisition with decreased neurogenesis. Multimodal profiling of m6A modification, YTHDF2 binding, and mRNA decay in hippocampal NSCs identified shared targets in multiple TGFβ signaling pathway components, including TGFβ ligands, maturation factors, receptors, transcription regulators, and signaling regulators. Functionally, Ythdf2 deletion led to TGFβ signaling activation in NSCs, suppression of which rescued elevated quiescence acquisition of proliferating hippocampal NSCs. Our study reveals the dynamic nature and critical roles of mRNA decay in establishing the quiescent adult hippocampal NSC pool and uncovers a novel mode of epitranscriptomic control via co-regulation of multiple components of the same signaling pathway. Comparative gene expression profiling analysis of RNA-seq and Decay-seq data for wild-type (WT) and Ythdf2-conditional-knockout (cKO) hippocampal neural stem cells (NSCs) cultured in vitro, as well as m6A-IP-Seq and YTHDF2-RIP-seq analysis of cultured WT NSCs.