The crosstalk between BMP and Wnt signaling establishes the equilibrium of villus length in mammalian small intestine

The precise regulatory mechanisms governing the quantitative balance of epithelial cells in the small intestine have long remained elusive. In this study, we reveal a gradual strengthening of BMP signaling from the proximal to distal segments. Through the utilization of genetically engineered mice, we demonstrate that BMP signaling plays a pivotal role in governing villus length. Furthermore, employing mathematical modeling, we uncover that BMP signaling acts as a cellular positional information sensor, orchestrating cell apoptosis and inhibiting cell proliferation. This collective regulation of cellular processes leads to the observed disparities in villus length between the proximal and distal segments of the small intestine. Notably, BMP signaling inhibits Wnt signaling to control the rate of villus growth, while Wnt signaling reciprocally upregulates BMP to maintain villus length under conditions of excessive proliferation. The spatial crosstalk between BMP and Wnt signaling networks collectively ensures the homeostasis of villus length. Our comprehensive investigation of the key factors underlying the gradient differences in villus length provides crucial insights for a deeper understanding of the functional dynamics of the small intestine.