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

Deivid Carvalho Rodrigues,Guang Yang,Mengli Ren,Sarah L Erickson,David R Kaplan,Guiqiong He,Rejitha Suraj,Lamees Mohammad,James Ellis,Emily M Harvey,Hongrui Liu

doi:10.1038/s41467-020-15941-2

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.

Highlights

Gene regulation and metabolism are two fundamental processes that coordinate the selfrenewal and differentiation of neural precursor cells (NPCs) in the developing mammalian brain
We have previously shown that methylglyoxal-metabolizing enzyme glyoxalase 1 (Glo1) maintains NPC homeostasis, thereby preventing premature neurogenesis in the developing murine cortex[20]
MG-H1 production was gradually increased in newborn neurons migrating in the intermediate zone (IZ) and became highly enriched in the cortical plate (CP), where it accumulated in the nuclei of neurons expressing neuronal markers βIII-tubulin and Brn[1] (Fig. 1a, b, Supplementary Fig. 1a)

Summary

Introduction

Gene regulation and metabolism are two fundamental processes that coordinate the selfrenewal and differentiation of neural precursor cells (NPCs) in the developing mammalian brain. During the development of the mammalian brain, neural precursor cells (NPCs) self-renew and differentiate to give rise to appropriate numbers of neurons[1] Key to this balance of self-renewal and differentiation is the crosstalk between gene expression and metabolism, two fundamental processes that co-ordinate NPC fate decision[2,3,4]. NPCs rely on glycolysis, their mitochondria exhibit an elongated morphology and are functional, with a forced metabolic switch to mitochondrial oxidative phosphorylation enhancing their differentiation[7,8] These observations reveal the reciprocal nature of the relationship between metabolism and gene expression critical for NPC fate decision. We have recently found that an increase in methylglyoxal levels depletes NPC numbers in the developing mouse cortex[20], raising the possibility that methylglyoxal may serve as a metabolic signal to regulate specific genes for NPC homeostasis by modulating RNA-binding enzymes such as GAPDH. This study provides a mechanistic link for the metabolic regulation of gene expression in NPC homeostasis

Methods

Results

Conclusion