Glycolytic flux-signaling controls mouse embryo mesoderm development
- European Molecular Biology Laboratory, Germany
- German Cancer Research Center, Germany
- University of Southampton, United Kingdom
- University of Copenhagen, Denmark
- University Hospital Heidelberg, Germany
- University of Cambridge, United Kingdom
- Max Planck Institute of Biophysics, Germany
Abstract
How cellular metabolic state impacts cellular programs is a fundamental, unresolved question. Here we investigated how glycolytic flux impacts embryonic development, using presomitic mesoderm (PSM) patterning as the experimental model. First, we identified fructose 1,6-bisphosphate (FBP) as an in vivo sentinel metabolite that mirrors glycolytic flux within PSM cells of post-implantation mouse embryos. We found that medium-supplementation with FBP, but not with other glycolytic metabolites, such as fructose 6-phosphate and 3-phosphoglycerate, impaired mesoderm segmentation. To genetically manipulate glycolytic flux and FBP levels, we generated a mouse model enabling the conditional overexpression of dominant active, cytoplasmic PFKFB3 (cytoPFKFB3). Overexpression of cytoPFKFB3 indeed led to increased glycolytic flux/FBP levels and caused an impairment of mesoderm segmentation, paralleled by the downregulation of Wnt-signaling, reminiscent of the effects seen upon FBP-supplementation. To probe for mechanisms underlying glycolytic flux-signaling, we performed subcellular proteome analysis and revealed that cytoPFKFB3 overexpression altered subcellular localization of certain proteins, including glycolytic enzymes, in PSM cells. Specifically, we revealed that FBP supplementation caused depletion of Pfkl and Aldoa from the nuclear-soluble fraction. Combined, we propose that FBP functions as a flux-signaling metabolite connecting glycolysis and PSM patterning, potentially through modulating subcellular protein localization.
Data availability
RNAseq data have been deposited to the European Nucleotide Archive (ENA) under the accession number PRJEB55095.
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Funding
European Molecular Biology Laboratory
- Kiran R Patil
- Martin Beck
- Alexander Aulehla
European Molecular Biology Laboratory
- Martin Beck
European Molecular Biology Laboratory
- Alexander Aulehla
H2020 Marie Skłodowska-Curie Actions (664726)
- Hidenobu Miyazawa
H2020 Marie Skłodowska-Curie Actions (664726)
- Hidenobu Miyazawa
- Henrik M Hammarén
Japan Society for the Promotion of Science
- Hidenobu Miyazawa
Sigrid Juséliuksen Säätiö
- Henrik M Hammarén
Deutsche Forschungsgemeinschaft (331351713)
- Alexander Aulehla
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animals were housed in the EMBL animal facility under veterinarians' supervision and were treated following the guidelines of the European Commission, revised directive 2010/63/EU and AVMA guidelines 2007. All the animal experiments were approved by the EMBL Institutional Animal Care and Use Committee (project code: 21-001_HD_AA).
Copyright
© 2022, Miyazawa et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Glycolytic flux-signaling controls mouse embryo mesoderm development
eLife 11:e83299.
https://doi.org/10.7554/eLife.83299
