美国宾夕法尼亚大学Hongjun Song等研究人员合作发现，m6A/YTHDF2介导的mRNA降解靶向TGF-β信号通路，来抑制早期出生小鼠海马神经干细胞的静息状态获得。该研究于2024年10月29日在线发表于国际一流学术期刊《细胞—干细胞》。

研究人员展示了在早期出生小鼠海马中条件性删除m⁶A阅读蛋白Ythdf2（促进mRNA降解），如何以细胞自主的方式提高静息状态获得，同时降低神经发生。对海马神经干细胞（NSC）中m⁶A修饰、YTHDF2结合和mRNA降解的多模式分析，识别了多个转化生长因子β（TGF-β）信号通路成分的共享靶标，包括TGF-β配体、成熟因子、受体、转录调节因子和信号调节因子。

功能性实验表明，Ythdf2的缺失导致NSC中TGF-β信号的激活，而抑制该信号可以挽救增殖海马NSC的静息状态获得升高。该研究揭示了mRNA降解在建立静息成年海马NSC库中的动态性质和关键作用，并揭示了一种通过共同调控同一信号通路多个成分的，不同表观转录组控制模式。

据介绍，增殖NSC获得静息状态是建立成年NSC库所必需的。然而，其背后的分子机制尚不清楚。

附：英文原文

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

Author: 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

Issue&Volume: 2024-10-29

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.

DOI: 10.1016/j.stem.2024.10.002

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00364-3