Villification of the intestinal epithelium is driven by Foxl1 through activation of PDGFRα and BMPs.

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.