Department of Genetics and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cells Dev. 2021 Mar;165:203662. doi: 10.1016/j.cdev.2021.203662. Epub 2021 Jan 28.
Wnt5a is a non-canonical Wnt ligand that is essential for normal embryonic development in mammals. The role of Wnt5a in early intestinal development has been examined in gene ablation models, where Wnt5a mice exhibit strikingly shortened intestines. However, the exact cellular source of Wnt5a has remained elusive, until a recent study found that FoxL1-expressing mesenchymal cells (FoxL1 cells), which are localized directly beneath the intestinal epithelium, express Wnt5a. To determine whether FoxL1 cells are a required source of Wnt5a during intestinal development, we derived FoxL1-Cre; Wnt5a mice, which is the first mouse model to ablate Wnt5a in a cell type-specific manner in the intestine in vivo. Our results show that Wnt5a deletion in FoxL1 cells during fetal life causes a shortened gut phenotype in neonatal mice, and that our model is sufficient to increase rate of apoptosis in the elongating epithelium, thus explaining the shortened gut phenotype. However, in contrast to previous studies using Wnt5a null mice, we did not observe dysregulation of epithelial structure or apical-basal protein localization. Altogether, our findings establish a developmental role for FoxL1 mesenchymal cells in controlling non-canonical Wnt signaling during midgut elongation.
Wnt5a 是一种非经典的 Wnt 配体，对于哺乳动物的正常胚胎发育至关重要。Wnt5a 在早期肠道发育中的作用已经在基因敲除模型中进行了研究，在这些模型中，Wnt5a 小鼠表现出明显缩短的肠道。然而，Wnt5a 的确切细胞来源一直难以捉摸，直到最近的一项研究发现，FoxL1 表达的间充质细胞（FoxL1 细胞），位于肠道上皮细胞的正下方，表达 Wnt5a。为了确定 FoxL1 细胞在肠道发育过程中是否是 Wnt5a 的必需来源，我们构建了 FoxL1-Cre; Wnt5a 小鼠，这是第一个在体内以细胞类型特异性方式在肠道中特异性敲除 Wnt5a 的小鼠模型。我们的结果表明，在胎儿期 FoxL1 细胞中缺失 Wnt5a 会导致新生小鼠的肠道缩短表型，并且我们的模型足以增加伸长上皮细胞的凋亡率，从而解释了肠道缩短的表型。然而，与之前使用 Wnt5a 缺失小鼠的研究相比，我们没有观察到上皮结构或顶端-基底蛋白定位的失调。总之，我们的研究结果确立了 FoxL1 间充质细胞在控制中肠伸长过程中非经典 Wnt 信号传导中的发育作用。
