Program in Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
Department of Medical Genetics, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Nat Commun. 2020 Apr 24;11(1):2018. doi: 10.1038/s41467-020-15941-2.
Gene regulation and metabolism are two fundamental processes that coordinate the self-renewal and differentiation of neural precursor cells (NPCs) in the developing mammalian brain. However, little is known about how metabolic signals instruct gene expression to control NPC homeostasis. Here, we show that methylglyoxal, a glycolytic intermediate metabolite, modulates Notch signalling to regulate NPC fate decision. We find that increased methylglyoxal suppresses the translation of Notch1 receptor mRNA in mouse and human NPCs, which is mediated by binding of the glycolytic enzyme GAPDH to an AU-rich region within Notch1 3'UTR. Interestingly, methylglyoxal inhibits the enzymatic activity of GAPDH and engages it as an RNA-binding protein to suppress Notch1 translation. Reducing GAPDH levels or restoring Notch signalling rescues methylglyoxal-induced NPC depletion and premature differentiation in the developing mouse cortex. Taken together, our data indicates that methylglyoxal couples the metabolic and translational control of Notch signalling to control NPC homeostasis.
基因调控和代谢是协调哺乳动物大脑发育过程中神经前体细胞（NPC）自我更新和分化的两个基本过程。然而，人们对代谢信号如何指导基因表达来控制 NPC 稳态知之甚少。在这里，我们表明，糖酵解中间代谢产物甲基乙二醛（methylglyoxal）调节 Notch 信号通路以调节 NPC 命运决定。我们发现，甲基乙二醛增加会抑制小鼠和人类 NPC 中 Notch1 受体 mRNA 的翻译，这是由糖酵解酶 GAPDH 与 Notch1 3'UTR 内的富含 AU 的区域结合介导的。有趣的是，甲基乙二醛抑制 GAPDH 的酶活性，并将其作为 RNA 结合蛋白来抑制 Notch1 翻译。降低 GAPDH 水平或恢复 Notch 信号通路可挽救甲基乙二醛诱导的发育中的小鼠皮质 NPC 耗竭和过早分化。总之，我们的数据表明，甲基乙二醛将 Notch 信号的代谢和翻译控制联系起来，以控制 NPC 稳态。
