Program in Developmental & Stem Cell Biology, the Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Program in Developmental & Stem Cell Biology, the Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3G8, Canada.
Dev Cell. 2020 Mar 9;52(5):647-658.e6. doi: 10.1016/j.devcel.2020.02.003.
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，肠道上皮经历了由间质信号介导的剧烈形态发生，形成绒毛，这对于有效吸收营养和宿主防御是必需的。尽管平滑肌诱导的物理力和间质细胞在新出现的绒毛下的聚集都与上皮折叠有关，但潜在的细胞机制尚不清楚。Hedgehog (Hh) 信号可以介导这两个过程。因此，我们分析了它的直接靶标组，并揭示了 GLI2 对非典型钙粘蛋白和平面细胞极性 (PCP) 基因的转录激活。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。对 PCP 突变小鼠的分析和遗传相互作用研究表明，Fat4-Dchs1 轴与核心-Vangl2 PCP 轴平行作用，以控制间质细胞的聚集。此外，活光片荧光显微镜和培养的 PDGFRα+细胞显示，PCP 在其由 WNT5A 引导的定向细胞迁移中是必需的。因此，由 Hh 信号诱导的间质 PCP 驱动细胞聚集和随后的上皮重塑。
