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


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 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.

SUBMITTER: Rodrigues DC 

PROVIDER: S-EPMC7181744 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Rodrigues Deivid Carvalho DC   Harvey Emily M EM   Suraj Rejitha R   Erickson Sarah L SL   Mohammad Lamees L   Ren Mengli M   Liu Hongrui H   He Guiqiong G   Kaplan David R DR   Ellis James J   Yang Guang G  

Nature communications 20200424 1


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  ...[more]

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