Abstract
The primitive gut tube of mammals initially forms as a simple cylinder consisting of the endoderm-derived, pseudostratified epithelium and the mesoderm-derived surrounding mesenchyme. During mid-gestation, a dramatic transformation occurs in which the epithelium is both restructured into its final cuboidal form and simultaneously folded and refolded to create intestinal villi and intervillus regions. Here, we show that the mesenchymal winged helix transcription factor Foxl1, itself induced by epithelial hedgehog signaling, controls villification by activating BMP and PDGFRα and the planar cell polarity factor Fat4 in epithelial-adjacent telocyte progenitors either directly or indirectly. In the absence of Foxl1-dependent mesenchymal signaling, villus formation and the separation of epithelial cells into mitotic intervillus and postmitotic villus are delayed, and the differentiation of secretory progenitors temporarily blocked. Thus, Foxl1 orchestrates key events during the epithelial transition of the fetal mammalian gut.
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Data availability
The single-cell RNA sequencing datasets generated in this study are available in the NCBI Gene Expression Omnibus (GEO) under accession number GSE302290. A source data file is provided. All other relevant data supporting the findings of this study are available from the corresponding author upon request. Source data are provided with this paper.
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Acknowledgements
We thank members of the Kaestner lab for helpful discussions. This work was supported by NIH grants R37DK053839 and R01DK139049. We thank the UPenn Center for Molecular Studies in Digestive and Liver Diseases (P30 DK050306) for the use of the Molecular Pathology and Imaging Core (MPIC) for tissue processing, the UPenn Diabetes Research Center Functional Genomics Core (P30 DK019125) for help with data analysis, and Yuri Veklich from the Cell & Developmental Biology Microscopy Core in the UPenn Department of Cell Biology for the use of their scanning electron microscope and confocal imaging services.
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G.Z. and K.H.K.—Conceptualization and writing. G.Z., G.R., K.B., M.T., L.C. and D.L.—Methodology. G.Z. and J.S.—Data curation and visualization. K.H.K.—Supervision. K.H.K.—Funding acquisition.
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Zhu, G., Rozenberg, G., Lahori, D. et al. Villification of the intestinal epithelium is driven by Foxl1 through activation of PDGFRα and BMPs. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69791-5
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DOI: https://doi.org/10.1038/s41467-026-69791-5
