During development, intestinal epithelia undergo dramatic morphogenesis mediated by mesenchymal signaling to form villi, which are required for efficient nutrient absorption and host defense. Although both smooth-muscle-induced physical forces and mesenchymal cell clustering beneath emerging villi are implicated in epithelial folding, the underlying cellular mechanisms are unclear. Hedgehog (Hh) signaling can mediate both processes. We therefore analyzed its direct targetome and revealed GLI2 transcriptional activation of atypical cadherin and planar cell polarity (PCP) genes. By examining Fat4 and Dchs1 knockout mice, we demonstrate their critical roles in villus formation. Analyses of PCP-mutant mice and genetic interaction studies show that the Fat4-Dchs1 axis acts in parallel to the core-Vangl2 PCP axis to control mesenchymal cell clustering. Moreover, live light-sheet fluorescence microscopy and cultured PDGFRα+ cells reveal a requirement for PCP in their oriented cell migration guided by WNT5A. Therefore, mesenchymal PCP induced by Hh signaling drives cell clustering and subsequent epithelial remodeling.

在发育过程中，肠上皮细胞经历间充质信号传导介导的剧烈形态发生，形成绒毛，这是有效吸收养分和防御宿主所必需的。尽管平滑肌诱导的物理力和新生绒毛下方的间充质细胞聚集都与上皮折叠有关，但潜在的细胞机制尚不清楚。刺猬（Hh）信号可以介导这两个过程。因此，我们分析了其直接靶组，并揭示了非典型钙粘蛋白和平面细胞极性（PCP）基因的GLI2转录激活。通过检查Fat4和Dchs1敲除小鼠，我们证明了它们在绒毛形成中的关键作用。PCP突变小鼠的分析和遗传相互作用研究表明，Fat4-Dchs1轴平行于核心-Vangl2 PCP轴来控制间充质细胞聚集。此外，活体光片荧光显微镜法和培养的PDGFRα+细胞揭示了PCP在WNT5A指导的定向细胞迁移中的需求。因此，由Hh信号诱导的间充质PCP驱动细胞聚集和随后的上皮重塑。