Metabolic control of germ layer proportions through regulation of Nodal and Wnt signalling

Abstract

During embryonic development, cells exit pluripotency to give rise to the three germ layers. Metabolic pathways influence cell fate decisions by modulating the epigenetic, transcriptional, and signalling states of cells. However, the interplay between metabolism and the major signalling pathways that drive the emergence of ectoderm, mesoderm, and endoderm remains poorly understood. Here, we demonstrate an instructive role of glycolytic activity in activating signalling pathways involved in mesoderm and endoderm induction. Using an in vitro model system for mouse gastrulation, we observed that inhibiting glycolysis prevents the upregulation of primitive streak markers, resulting in a significant increase in ectodermal cell fates at the expense of mesodermal and endodermal lineages. We demonstrate that this relationship is dose-dependent, enabling metabolic control of germ layer proportions through exogenous glucose levels. Mechanistically, we found that glycolysis inhibition leads to the downregulation of Wnt, Nodal, and Fgf signalling. Notably, this metabolic phenotype was rescued by Nodal or Wnt signalling agonists in the absence of glycolytic activity, suggesting that glycolytic activity acts upstream of both signalling pathways. Our work underscores the dependence of specific signalling pathways on metabolic conditions and provides mechanistic insight into the nutritional regulation of cell fate decision making.

Systematic analysis of protein stability associated with species-specific developmental tempo

“…Given that both the ubiquitin-proteasome and autophagy-lysosome systems are multi-step processes that require ATP, lowering the ATP production rate may decelerate the rate-limiting steps of protein degradation. It should be noted, however, that glycolysis and its inhibitor 2DG also influence cellular signaling and glycosylation pathways 22,24,36,37 . Furthermore, the inhibition of glycolytic activity less effectively affected lysosome-mediated degradation compared with proteasome-mediated degradation, implying additional factors.…”

Metabolic activities are selective modulators for individual segmentation clock processes

“…As bio-energetic rates did not correlate with the segmentation clock period or key kinetic parameters, specific metabolites and metabolic factors that are regulated by distinct metabolic inhibitors, such as glycolytic metabolites and NAD+/NADH 26,36 , may modulate the individual processes. It is also noteworthy that many metabolic enzymes and metabolites have moonlighting functions affecting cellular signaling pathways in addition to the canonical bio-energetic function 34,36,38–40 , and that metabolic inhibitors can perturb other branches of metabolic pathways 41 . Clarifying the effectors of distinct metabolic inhibitions that modulate the three key molecular processes of the segmentation clock serves as an important future research avenue.…”

Metabolic mechanisms of species-specific developmental tempo

“… 47 , 48 In particular, intermediary metabolism has been found to generate metabolites that can act as signaling or modulating factors for various molecular processes, particularly in stem cell fate transitions and embryogenesis. 48 , 49 , 50 , 51 Mitochondria are at the core of the regulation and generation of many of these metabolites, and, as such, these organelles are increasingly recognized as key players in developmental and stem cell biology. 52 , 53 Could mitochondrial metabolism display species differences at the cellular level and thereby contribute to species-specific developmental features?…”