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Spatiotemporal proteomics reveals dynamic antiparallel gradients shaping signalling waves [Spatiotemporal RNAseq]

ABSTRACT: Embryonic development is driven by dynamic protein networks, yet how these dynamics shape morphogenesis remains poorly understood. Somitogenesis, the rhythmic segmentation of vertebrate embryos, is controlled by signalling gradients and oscillations in the presomitic mesoderm (PSM), but the underlying protein dynamics remain largely unknown. Here, we combine microfluidic synchronization of mouse embryo tails with quantitative proteomics and transcriptomics to resolve spatiotemporal protein dynamics during somitogenesis. We identify dynamic proteins not previously linked to somitogenesis and reveal an antiparallel, dynamic R-Spondin/LGR signalling pattern that explains how Wnt oscillation amplitude increases despite declining Wnt ligand levels in the anterior PSM. Dynamic ligand expression was validated in mouse gastruloids, and perturbation of ligand dynamics reduced oscillation amplitude and impaired somite formation. Together, our findings identify R-Spondin as a dynamic amplifier of Wnt signalling oscillations and provide a mechanistic framework for understanding how protein dynamics regulate mammalian tissue patterning.

ORGANISM(S): Mus musculus

PROVIDER: GSE304261 | GEO | 2026/09/01

REPOSITORIES: GEO

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Project description:Pluripotent stem cells (PSCs) have increasingly been used to model different aspects of embryogenesis and organ formation. Despite recent advances in the in vitro induction of major mesodermal lineages and mesoderm-derived cell types experimental model systems that can recapitulate more complex biological features of human mesoderm development and patterning are largely missing. Here, we utilized induced pluripotent stem cells (iPSCs) for the stepwise in vitro induction of presomitic mesoderm (PSM) and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modeling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We succeeded to observe oscillatory expression of core segmentation clock genes, including HES7 and DKK1, determined the period of the human segmentation clock to be around five hours and showed the presence of dynamic traveling wave-like gene expression within in vitro induced human PSM. We furthermore identified and compared oscillatory genes in human and murine PSC-derived PSM, which revealed species-specific as well as common molecular components and novel pathways associated with the mouse and human segmentation clocks. Utilizing CRISPR/Cas9-based genome editing technology, we then targeted genes, for which mutations in patients with segmentation defects of vertebrae (SDV) such as spondylocostal dysostosis (SCD) have been reported (e.g. HES7, LFNG, DLL3 and MESP2 DLL3). Subsequent analysis of patient-like knock-out and point-mutation lines as well as patient-derived iPSCs together with their genetically corrected isogenic controls revealed gene-specific alterations in oscillation, synchronization or differentiation properties, validating the overall utility of our model system, to provide novel insights into the human segmentation clock as well as diseases associated with the formation of the human axial skeleton.

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Spatiotemporal proteomics reveals dynamic antiparallel gradients shaping signalling waves [Spatiotemporal RNAseq]

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