Wnt/beta‐catenin signaling in patterning and differentiation of the vertebrate endoderm

The endoderm gives rise to organs as different in anatomy and function as the lungs, colon and liver, and we want to understand the signaling processes controlling this diversification. Our primary interest is in the pancreas, and our work indicates multiple roles for the Wnt/beta (β)‐catenin signaling pathway in its development. Early, Wnt signaling inhibits pancreas specification within the foregut; later, it promotes expansion of multipotent progenitor cells and their differentiation into exocrine acinar tissue. Until recently, our studies have focused on response to Wnt ligands, mediated by the non‐redundant functions of β‐catenin. To better understand the role of Wnt ligand production , while bypassing redundancy between the ligand‐encoding genes, we have targeted the mouse Porcn gene, homologous to Drosophila porcupine. Porcupine is required for wingless secretion and bioactivity, and we find that mouse cells lacking Porcn cannot produce any of several Wnt ligands tested, but retain normal responsiveness to exogenous Wnts. The Porcn mutant defect thus closely resembles that of fly porcupine , indicating a conserved and non‐redundant role for this gene in Wnt production. Wnt production by Porcn mutant cells is rescued by wildtype human PORCN , but not a PORCN mutant recently identified in a pleiotropic congenital syndrome, Focal Dermal Hypoplasia. Mice carrying a conditional Porcn allele are viable, and will provide a novel genetic tool to understand Wnt function in endoderm development and beyond. Supported by the NIH ( R01‐DK075072 ) and Searle Scholars Program (06‐B‐116).