Methylglyoxal couples metabolic and translational control of Notch signalling in mammalian neural stem cells.
3' Untranslated Regions
Animals
Brain
/ cytology
Cell Differentiation
Cell Line
Female
Gene Expression Regulation, Developmental
Glyceraldehyde-3-Phosphate Dehydrogenases
/ metabolism
HEK293 Cells
Humans
Mice
Neural Stem Cells
/ metabolism
Neurogenesis
/ genetics
Protein Biosynthesis
Pyruvaldehyde
/ metabolism
RNA, Messenger
/ metabolism
Receptor, Notch1
/ genetics
Signal Transduction
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 04 2020
24 04 2020
Historique:
received:
11
05
2019
accepted:
31
03
2020
entrez:
26
4
2020
pubmed:
26
4
2020
medline:
11
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32332750
doi: 10.1038/s41467-020-15941-2
pii: 10.1038/s41467-020-15941-2
pmc: PMC7181744
doi:
Substances chimiques
3' Untranslated Regions
0
NOTCH1 protein, human
0
Notch1 protein, mouse
0
RNA, Messenger
0
Receptor, Notch1
0
Pyruvaldehyde
722KLD7415
Glyceraldehyde-3-Phosphate Dehydrogenases
EC 1.2.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2018Subventions
Organisme : CIHR
ID : PJT-165821
Pays : Canada
Organisme : CIHR
ID : PJT-148746
Pays : Canada
Organisme : CIHR
ID : ERT161303
Pays : Canada
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