TY  - JOUR
AU  - Miyazawa, Hidenobu
AU  - Snaebjörnsson, Marteinn Thor
AU  - Prior, Nicole
AU  - Kafkia, Eleni
AU  - Hammarén, Henrik M
AU  - Tsuchida-Straeten, Nobuko
AU  - Patil, Kiran R
AU  - Beck, Martin
AU  - Aulehla, Alexander
TI  - Glycolytic flux-signaling controls mouse embryo mesoderm development.
JO  - eLife
VL  - 11
SN  - 2050-084X
CY  - Cambridge
PB  - eLife Sciences Publications
M1  - DKFZ-2022-02999
SP  - e83299
PY  - 2022
N1  - #EA:A410#
AB  - 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.
KW  - developmental biology (Other)
KW  - mouse (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36469462
DO  - DOI:10.7554/eLife.83299
UR  - https://inrepo02.dkfz.de/record/182896
ER  -