Methylglyoxal couples metabolic and translational control of Notch signalling in mammalian neural stem cells

Deivid Carvalho Rodrigues, Emily M. Harvey, Rejitha Suraj, Sarah L. Erickson, Lamees Mohammad, Mengli Ren, Hongrui Liu, Guiqiong He, David R. Kaplan, James Ellis and Guang Yang ()
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Deivid Carvalho Rodrigues: Hospital for Sick Children
Emily M. Harvey: University of Calgary
Rejitha Suraj: University of Calgary
Sarah L. Erickson: University of Calgary
Lamees Mohammad: University of Calgary
Mengli Ren: Chongqing Medical University
Hongrui Liu: University of Calgary
Guiqiong He: Chongqing Medical University
David R. Kaplan: Hospital for Sick Children
James Ellis: Hospital for Sick Children
Guang Yang: Hospital for Sick Children

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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 3ʹUTR. 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.

Date: 2020
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DOI: 10.1038/s41467-020-15941-2

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