FoxL1⁺ mesenchymal cells are a critical source of Wnt5a for midgut elongation during mouse embryonic intestinal...

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^f/f 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.