Glycolytic flux-responsive genes in mouse PSM cells
The question of how metabolism impacts embryonic development is seeing a renaissance. Whether metabolism exerts direct, instructive signaling functions is one of the central issues that need to be resolved. We tackled this question in the context of embryonic axis segmentation. Previous studies have shown that changes in central carbon metabolism impact Wnt signaling and the period of the segmentation clock, which controls the timing of axis segmentation. Here, we revealed that glycolysis tunes the segmentation clock period in an anticorrelated manner: higher glycolytic flux slows down the clock, and vice versa. Transcriptome and gene regulatory network analyses identified Wnt signaling as the potential mediator of flux-dependent control of the clock period. Critically, we revealed that deletion of the Wnt antagonist Dkk1 rescued the clock period phenotype without affecting glycolysis, demonstrating an instructive signaling role for glycolysis. Building on these findings, we further demonstrated the ability to synchronize the segmentation clock oscillations with transient glycolytic cues, specifically periodic changes in glucose or fructose 1,6-bisphosphate levels. Notably, this metabolic synchronization effect showed specificity, first entraining Wnt signaling oscillations. Combined, our work identifies a glycolysis-Wnt signaling axis that tunes developmental timing, highlighting the instructive role of metabolism in embryonic development.