Selective Utilisation of Glucose Metabolism Guides Mammalian Gastrulation

The prevailing dogma for morphological patterning in developing organisms argues that the combined inputs of transcription factor networks and signalling morphogens generate spatially and temporally distinct expression patterns1. However, recent work spanning multiple disciplines has highlighted the role of metabolic pathways as developmental regulators2-7, independent of energy production and growth. Yet, the mechanistic role of nutrient utilisation in instructing cellular programs to shape the in vivo developing mammalian embryo is unknown. Here, we discover two spatially-resolved waves of glucose metabolism in a cell type- and stage-specific manner in mammalian gastrulation by using quantitative live-imaging of developing mouse embryos at single-cell resolution, stem cell models, and embryo-derived tissue explants. By selectively inhibiting key enzymes involved in different branches of glucose metabolism, we identify that the first finely-tuned spatiotemporal wave of glucose metabolism occurs through the hexosamine biosynthetic pathway to drive fate acquisition in the epiblast, while the second wave uses glycolysis to support mesoderm migration and lateral expansion. Furthermore, we demonstrate that glucose exerts its influence on these developmental processes through cell signalling pathways, with distinct mechanisms connecting glucose with the ERK activity in each wave. Our findings underscore the integral role of cellular metabolism in guiding cell fate and specialized functions during development, interfacing with genetic mechanisms and morphogenic gradients. This study provides valuable insights into various developmental contexts including embryonic lethality, congenital disease, and cancer, challenging previous notions about the generic and housekeeping nature of cellular metabolism.