Selective utilization of glucose metabolism guides mammalian gastrulation

Dominica Cao, Jenna Bergmann, Liangwen Zhong, Anupama Hemalatha, Chaitanya Dingare, Tyler Jensen, Andy L. Cox, Valentina Greco, Benjamin Steventon and Berna Sozen ()
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Dominica Cao: Yale University
Jenna Bergmann: Yale University
Liangwen Zhong: Yale University
Anupama Hemalatha: Yale University
Chaitanya Dingare: Downing Site
Tyler Jensen: Yale University
Andy L. Cox: Yale University
Valentina Greco: Yale University
Benjamin Steventon: Downing Site
Berna Sozen: Yale University

Nature, 2024, vol. 634, issue 8035, 919-928

Abstract: Abstract The prevailing dogma for morphological patterning in developing organisms argues that the combined inputs of transcription factor networks and signalling morphogens alone generate spatially and temporally distinct expression patterns. However, metabolism has also emerged as a critical developmental regulator1–10, independent of its functions in energy production and growth. The mechanistic role of nutrient utilization in instructing cellular programmes to shape the in vivo developing mammalian embryo remains unknown. Here we reveal two spatially resolved, cell-type- and stage-specific waves of glucose metabolism during mammalian gastrulation by using single-cell-resolution quantitative imaging of developing mouse embryos, stem cell models and embryo-derived tissue explants. We identify that the first spatiotemporal wave of glucose metabolism occurs through the hexosamine biosynthetic pathway to drive fate acquisition in the epiblast, and the second wave uses glycolysis to guide mesoderm migration and lateral expansion. Furthermore, we demonstrate that glucose exerts its influence on these developmental processes through cellular signalling pathways, with distinct mechanisms connecting glucose with the ERK activity in each wave. Our findings underscore that—in synergy with genetic mechanisms and morphogenic gradients—compartmentalized cellular metabolism is integral in guiding cell fate and specialized functions during development. This study challenges the view of the generic and housekeeping nature of cellular metabolism, offering valuable insights into its roles in various developmental contexts.

Date: 2024
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DOI: 10.1038/s41586-024-08044-1

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