The cloacal outgrowth orchestrates co-development of the bladder and umbilical arteries

ABSTRACT The urinary bladder is an innovation of eutherian mammals to manage liquid waste. However, bladder development and its embryonic function remain poorly understood. Here, we report that in both humans and mice the bladder emerges from the cloaca as a rostral outgrowth, which is flanked by the umbilical arteries. Arrest of the outgrowth, as seen in Shh-null mouse embryos, causes bladder agenesis and unexpected severe defects of the umbilical arteries, suggesting that the outgrowth epithelial signal Shh coordinates development of both the bladder and the umbilical arteries. The signaling molecule Wnt2 is restricted to the rostral outgrowth mesenchyme and its expression is dramatically downregulated in Shh-null mutants. Furthermore, Wnt2-null mutants develop a small bladder and single umbilical artery defects. Collectively, we uncover an unexpected co-development mechanism of the bladder and umbilical arteries orchestrated by the cloacal outgrowth signals. The co-development paradigm offers a conceptual framework to understand evolution and development of the bladder.