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Axin1 and Axin2 cooperate to instruct mesodermal fates during mouse gastrulation

ABSTRACT: How distinct mesodermal lineages - extraembryonic, lateral, intermediate, paraxial and axial – are specified from pluripotent epiblast during gastrulation is a longstanding open question. By investigating Axin, a negative regulator of the WNT/b-catenin pathway, we uncover new roles for WNT signaling in the determination and segregation of extraembryonic, posterior lateral plate, and intermediate mesoderm fates. We undertook two complementary approaches to spatially and temporally dissect the role of WNT signaling at gastrulation. We augmented detailed analysis of Axin1;Axin2 mutant mouse embryos, including single-cell and single-embryo transcriptomics, with in vitro Epiblast-Like Cell (EpiLC) differentiation assays, which allowed us to reveal how coordinated activities of the WNT/b-catenin and BMP/pSmad1/5/9 pathways activate mesoderm lineage-specific programs. Our findings lead us to propose that Axin1 and Axin2 act to prevent aberrant differentiation of epiblast cells into extraembryonic, intermediate, paraxial and axial mesoderm, by spatially and temporally regulating levels of WNT signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE275548 | GEO | 2026/06/01

REPOSITORIES: GEO

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Project description:Mammalian genomes are subjected to epigenetic modifications, including cytosine methylation by DNA methyltransferases (Dnmt) and further oxidation by Ten-eleven-translocation (Tet) family of dioxygenases. Cytosine methylation plays key roles in multiple processes such as genomic imprinting and X-chromosome inactivation. However, the functional significance of cytosine methylation and the further oxidation has remained undetermined in mouse embryogenesis. Here we show that global inactivation of all three Tet genes in mice led to consistent defects in gastrulation. The defects include reduced specification of the axial mesoderm and paraxial mesoderm, mimicking phenotypes in embryos with gain-of-function Nodal signaling, a cardinal cue for gastrulation. Introduction of a single mutant allele of Nodal in the Tet mutant background partially restored patterning, suggesting that hyperactive Nodal signaling is a leading cause for the gastrulation failure of Tet mutants. Increased Nodal signaling is likely due to diminished expression of the Lefty1 and Lefty2 genes, inhibitors of Nodal signaling. Moreover, reduction in the Lefty gene expression can be ascribed to elevated DNA methylation as both Lefty-Nodal signaling and normal morphogenesis are largely restored in Tet-deficient embryos when the Dnmt3a and Dnmt3b genes are disrupted. Additionally, specific inactivation of Tet by point mutations abolishing the dioxygenase activity causes similar molecular and gastrulation abnormalities. Taken together, our results show that Tet-mediated DNA oxidation modulates the Lefty-Nodal signaling by promoting demethylation of the shared target genes with Dnmt3a and Dnmt3b. These findings reveal a fundamental epigenetic mechanism featuring dynamic DNA methylation and demethylation and their role in the regulation of key signaling in body plan formation during early embryogenesis. Examine RNA expression and DNA methylation differences between Tet-null and wild type samples of mouse epiblast in E6.5.

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Axin1 and Axin2 cooperate to instruct mesodermal fates during mouse gastrulation

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