A Spatiotemporal Compartmentalization of Glucose Metabolism Guides Mammalian Gastrulation Progression

Abstract

Gastrulation is considered the sine qua non of embryogenesis, establishing a multidimensional structure and the spatial coordinates upon which all later developmental events transpire. At this time, the embryo adopts a heavy reliance on glucose metabolism to support rapidly accelerating changes in morphology, proliferation, and differentiation. However, it is currently unknown how this conserved metabolic shift maps onto the three-dimensional landscape of the growing embryo and whether it is spatially linked to the orchestrated cellular and molecular processes necessary for gastrulation. Here we identify that glucose is utilised during mouse gastrulation via distinct metabolic pathways to instruct local and global embryonic morphogenesis, in a cell type and stage-specific manner. Through detailed mechanistic studies and quantitative live imaging of mouse embryos, in parallel with tractable in vitro stem cell differentiation models and embryo-derived tissue explants, we discover that cell fate acquisition and the epithelial-to-mesenchymal transition (EMT) relies on the Hexosamine Biosynthetic Pathway (HBP) branch of glucose metabolism, while newly-formed mesoderm requires glycolysis for correct migration and lateral expansion. This regional and tissue-specific difference in glucose metabolism is coordinated with Fibroblast Growth Factor (FGF) activity, demonstrating that reciprocal crosstalk between metabolism and growth factor signalling is a prerequisite for gastrulation progression. We expect these studies to provide important insights into the function of metabolism in other developmental contexts and may help uncover mechanisms that underpin embryonic lethality, cancer, and congenital disease.

Integrated Molecular-Phenotypic Profiling Reveals Metabolic Control of Morphological Variation in Stembryos

“…Recent work investigated the role of glucose metabolism during mouse peri-gastrulation stages using (st)embryos. 51,39 One study showed that during early gastrulation (∼E6.5 - ∼E7.25) mesoderm fate acquisition and maintenance is governed by glucose metabolism via the Hexosamine Biosynthetic Pathway (HBP), but mesoderm migration and lateral expansion requires glycolysis. 51 Complementary work in gastruloids suggested that mannose, but not glycolysis, is crucial for the early induction of T .…”

“…51,39 One study showed that during early gastrulation (∼E6.5 - ∼E7.25) mesoderm fate acquisition and maintenance is governed by glucose metabolism via the Hexosamine Biosynthetic Pathway (HBP), but mesoderm migration and lateral expansion requires glycolysis. 51 Complementary work in gastruloids suggested that mannose, but not glycolysis, is crucial for the early induction of T . 39 While at first glance some of these findings seem at odds with our discoveries, most of the effects we report here relate to later developmental stages (embryo equivalent: ∼E7.5-E9 4 ), during which mesoderm and neural cells are specified from a pool of NMPs.…”

Gastruloids — a minimalistic model to study complex developmental metabolism

“…Together, the results point to a critical role for mannose-dependent glycosylation for proper mesoderm specification in gastruloids [ 36 ]. This in vitro study was complemented by an in vivo dataset, also highlighting the role of glycosylation in mesoderm specification during gastrulation [ 37 ].…”

“…As various forms of NAD serve as cofactors in various oxidoreductive reactions, their relative fluorescence intensity can used as a readout of a particular metabolic state of cells within a tissue. Recently, it has been shown a posterior–anterior gradient of NAD(P)H in the gastrulating mouse embryo [ 37 ]. One limitation is such cofactors are produced and utilised in a wide range of pathways and again this makes it difficult to gain a spatial information on the actual metabolic state of cell in situ .…”