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Mesenchymal-epithelial interaction guides development of stomach and intestine in mouse embryos

ABSTRACT: After gut tube patterning in early embryos, the cellular and molecular changes of developing stomach and intestine remain largely unknown. Here, combining single-cell RNA-sequencing and spatial RNA-sequencing, we constructed a spatiotemporal transcriptomic landscape of the mouse stomach and intestine during embryonic day E9.5-E15.5. We observed regionalization and heterogeneity of both the epithelium and mesenchyme in the gastrointestinal (GI) tract at E9.5 and dynamic cell evolution afterwards. The spatiotemporal distributions of cell clusters and the epithelium-mesenchyme interactions indicate a coordinated development of the epithelium and mesenchyme. The cell evolution and signaling events regulate the stomach regionalization and intestine segmentation. Using the gut tube-derived organoids, we found that the cell fate of the foregut and hindgut could be switched by the regional niche factors. Together, this work demonstrates the important function of the epithelium-mesenchyme interactions in early GI tract development, laying a foundation for further dissection of the mechanisms governing this process.

ORGANISM(S): Mus musculus

PROVIDER: GSE186525 | GEO | 2022/07/12

REPOSITORIES: GEO

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Project description:Diverse functions of the homeodomain transcription factor BARX1 include Wnt-dependent, non-cell autonomous specification of the stomach epithelium, tracheo-bronchial septation, and Wnt-independent expansion of the spleen primordium. Tight spatio-temporal regulation of Barx1 levels in the mesentery and stomach mesenchyme suggests additional roles. To determine these functions, we forced constitutive BARX1 expression in the Bapx1 expression domain, which includes the mesentery and intestinal mesenchyme, and also examined Barx1-/- embryos in further detail. Transgenic embryos invariably showed intestinal truncation and malrotation, in part reflecting abnormal left-right patterning. Ectopic BARX1 expression did not affect intestinal epithelium, but intestinal smooth muscle developed with features typical of the stomach wall. BARX1, which is normally restricted to the developing stomach, drives robust smooth muscle expansion in this organ by promoting proliferation of myogenic progenitors at the expense of other sub-epithelial cells. Undifferentiated embryonic stomach and intestinal mesenchyme showed modest differences in mRNA expression and BARX1 was sufficient to induce much of the stomach profile in intestinal cells. However, limited binding at cis-regulatory sites implies that BARX1 may act principally through other transcription factors. Genes expressed ectopically in BARX1+ intestinal mesenchyme and reduced in Barx1-/- stomach mesenchyme include Isl1, Pitx1, Six2 and Pitx2, transcription factors known to control left-right patterning and influence smooth muscle development. The sum of evidence suggests that potent BARX1 functions in intestinal rotation and stomach myogenesis occur through this small group of intermediary transcription factors. To investigate how Barx1 regulates gut smooth muscle development in a cell-autonomous manner, we used Affymetrix arrays to profile genes enriched in wild-type stomach and BARX1-overexpressing intestinal mesenchyme, compared to wild-type intestinal mesenchyme.

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Mesenchymal-epithelial interaction guides development of stomach and intestine in mouse embryos

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