RNA 结合蛋白 (RBP) 控制神经元中信使 RNA 的命运。在这里，我们报告了一种机制，即刺激诱导的神经元翻译是由 YTHDF1 结合蛋白 FMRP 的磷酸化介导的。从机制上讲，YTHDF1 可以与核糖体蛋白缩合，促进其 mRNA 靶标的翻译。 FMRP 通过将 YTHDF1 与核糖体隔离来调节这一过程；在神经元刺激后，FMRP 被磷酸化并释放 YTHDF1 以进行翻译上调。我们证明，YTHDF1 的新型小分子抑制剂可以逆转类器官模型中与 FMRP 缺陷相关的脆性 X 综合征 (FXS) 发育缺陷。因此，我们的研究表明，FMRP 及其磷酸化是神经元发育和刺激过程中活动依赖性翻译的重要调节因子，并将 YTHDF1 确定为 FXS 的潜在治疗靶点，其中 FMRP 耗竭引起的发育缺陷可以通过 YTHDF1 抑制来逆转。版权所有 © 2023爱思唯尔公司保留所有权利。

RNA-binding proteins (RBPs) control messenger RNA fate in neurons. Here, we report a mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Mechanistically, YTHDF1 can condense with ribosomal proteins to promote the translation of its mRNA targets. FMRP regulates this process by sequestering YTHDF1 away from the ribosome; upon neuronal stimulation, FMRP becomes phosphorylated and releases YTHDF1 for translation upregulation. We show that a new small molecule inhibitor of YTHDF1 can reverse fragile X syndrome (FXS) developmental defects associated with FMRP deficiency in an organoid model. Our study thus reveals that FMRP and its phosphorylation are important regulators of activity-dependent translation during neuronal development and stimulation and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.Copyright © 2023 Elsevier Inc. All rights reserved.