m6A/YTHDF2-mediated mRNA decay targets TGF-β signaling to suppress the quiescence acquisition of early postnatal mouse hippocampal NSCs

Feng Zhang; Yao Fu; Dennisse Jimenez-Cyrus; Ting Zhao; Yachen Shen; Yusha Sun; Zhijian Zhang; Qing Wang; Riki Kawaguchi; Daniel H Geschwind; Chuan He; Guo-Li Ming; Hongjun Song

doi:10.1016/j.stem.2024.10.002

m⁶A/YTHDF2-mediated mRNA decay targets TGF-β signaling to suppress the quiescence acquisition of early postnatal mouse hippocampal NSCs

Cell Stem Cell. 2024 Oct 22:S1934-5909(24)00364-3. doi: 10.1016/j.stem.2024.10.002. Online ahead of print.

Authors

Feng Zhang¹, Yao Fu², Dennisse Jimenez-Cyrus³, Ting Zhao³, Yachen Shen³, Yusha Sun³, Zhijian Zhang³, Qing Wang⁴, Riki Kawaguchi⁴, Daniel H Geschwind⁴, Chuan He⁵, Guo-Li Ming⁶, Hongjun Song⁷

Affiliations

¹ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, USA; School of Life Sciences, Nanjing University, Nanjing, PRC.
² Department of Biology, School of Art and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Chemistry, Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA.
⁶ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: gming@pennmedicine.upenn.edu.
⁷ Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA; The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Neurosurgery, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: shongjun@pennmedicine.upenn.edu.

PMID: 39476834
DOI: 10.1016/j.stem.2024.10.002

Abstract

Quiescence acquisition of proliferating neural stem cells (NSCs) is required to establish the adult NSC pool. 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 elevated quiescence acquisition in a cell-autonomous fashion with decreased neurogenesis. Multimodal profiling of m⁶A modification, YTHDF2 binding, and mRNA decay in hippocampal NSCs identified shared targets in multiple transforming growth factor β (TGF-β)-signaling-pathway components, including TGF-β ligands, maturation factors, receptors, transcription regulators, and signaling regulators. Functionally, Ythdf2 deletion led to TGF-β-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 distinct mode of epitranscriptomic control via co-regulation of multiple components of the same signaling pathway.

Keywords: TGF-β; Ythdf2; adult neural stem cell establishment; co-regulation; epitranscriptomics; hippocampus; m(6)A; mRNA decay; quiescence.