Yap mediates Hippo signaling to balance proliferation and differentiation in the developing glandular stomach epithelium

The glandular stomach is an important digestive organ, and its proper epithelial development is essential for its normal structure and function. However, the molecular mechanisms underlying its epithelial development remain largely unclear. Here, we employ mouse genetics to reveal that Hippo signaling regulates stomach epithelial development by balancing epithelial proliferation and differentiation. Deletion of Yap reduces epithelial growth in the developing glandular stomach, whereas overexpression of constitutively active Yap promotes its expansion. Single-cell RNA sequencing (scRNA-seq) and histological analyses further show that Yap enhances gastric epithelial proliferation while suppressing differentiation. Using 3D organoids, we find that Yap directly governs gastric epithelial proliferation and differentiation. Further genetic studies reveal that Mst1/2 deficiency regulates glandular stomach development partially through Yap. Finally, we demonstrate that Yap controls gastric epithelial proliferation and differentiation by modulating cell cycle activity. Overall, our studies demonstrate that Hippo signaling plays an important role in fine-tuning stomach development.