Repression of Wnt/β-catenin signaling in the anterior endoderm is essential for liver and pancreas development

The liver and pancreas are specified from the foregut endoderm through an interaction with the adjacent mesoderm. However, the earlier molecular mechanisms that establish the foregut precursors are largely unknown. In this study, we have identified a molecular pathway linking gastrula-stage endoderm patterning to organ specification. We show that in gastrula and early-somite stage Xenopus embryos, Wnt/beta-catenin activity must be repressed in the anterior endoderm to maintain foregut identity and to allow liver and pancreas development. By contrast, high beta-catenin activity in the posterior endoderm inhibits foregut fate while promoting intestinal development. Experimentally repressing beta-catenin activity in the posterior endoderm was sufficient to induce ectopic organ buds that express early liver and pancreas markers. beta-catenin acts in part by inhibiting expression of the homeobox gene hhex, which is one of the earliest foregut markers and is essential for liver and pancreas development. Promoter analysis indicates that beta-catenin represses hhex transcription indirectly via the homeodomain repressor Vent2. Later in development, beta-catenin activity has the opposite effect and enhances liver development. These results illustrate that turning Wnt signaling off and on in the correct temporal sequence is essential for organ formation, a finding that might directly impact efforts to differentiate liver and pancreas tissue from stem cells.