Metabolic signaling mechanisms controlling mammalian embryonic patterning

SUMMARY: Gastrulation is a pivotal event in early development, establishing the body plan and shaping future tissues. Even slight alterations in this process can lead to embryonic or fetal lethality, or developmental defects. While traditionally viewed as a passive energy source, recent studies—including our own—reveal that glucose metabolism instructively regulates development. Our findings in mouse embryos show that co-developing epiblast and mesoderm cells rely on distinct branches of glucose metabolism to drive cell fate transitions and subsequent cell movements. Further, we identified specific metabolic intermediates that are selectively required to instruct distinct developmental outcomes, by modulating FGF/ERK signaling. In this proposal, we will combine multi-omics approaches in mouse embryos, embryo-derived tissue explants and in vitro stem cell-based embryo models to uncover how glucose, as a single nutrient, spatially coordinates signaling networks, protein function, and gene expression to drive lineage-specific fate decisions (Aim 1) and morphogenetic behaviors (Aim 2) by generating distinct metabolic intermediates that regulate ERK signaling during mammalian gastrulation. In Aim 1, we perform cell type-resolved isotope tracing and employ 3D high-resolution two-photon live imaging in transgenic reporter mouse embryos to simultaneously track cellular metabolic states and ERK signaling activity in embryonic domains. Building on our preliminary results, we will test the hypothesis that glycosylation via the Hexosamine Biosynthetic Pathway (HBP) acts as a key metabolic mechanism linking glucose flux to ERK activation during the epiblast-to-mesoderm transition. Using proteomics assays and genetic perturbations, we will determine how HBP-driven glycosylation regulates ERK-dependent mesoderm specification. In Aim 2, guided by our preliminary results, we will establish a direct causal relationship between localized lactate production and ERK functionality in mesodermal migration and subsequent developmental progression. We will analyze how glycolysis-driven lactylation regulates key transcription factor and signaling proteins during mesodermal development, employing integrative genomic, proteomic, and functional analyses. These studies will reveal how spatially regulated glucose metabolism shapes developmental trajectories at the intersection of metabolic and signaling networks. By completion of this study, we expect to discover key metabolic mechanisms that instruct local and global embryo morphogenesis and patterning during gastrulation, and the consequences on early developmental patterning when these processes go awry. The advances will provide insights into how progenitor-level defects induced by metabolite availability may cause pregnancy loss and developmental disorders in humans. Project Number: 1R01HD117902-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Berna Sozen | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $627,603 | Activity Code: R01 | Study Section: Development - 2 Study Section[DEV2] View on NIH RePORTER: https://reporter.nih.gov/project-details/11295680