Hippo signaling regulates pancreas development through inactivation of

Themammalian pancreas is required for normal metabolism, with defects in this vital organ commonly observed in cancer and diabetes. Development must therefore be tightly controlled in order to produce a pancreas of correct size, cell type composition, and physiologic function. Through negative regulation of Yap-dependent proliferation, the Hippo kinase cascade is a critical regulator of organ growth. To investigate the role of Hippo signaling in pancreas biology, we deleted Hippo pathway compo-nents in the developing mouse pancreas. Unexpectedly, the pancreas fromHippo-deficient offspring was reduced in size, with defects evident throughout the organ. Increases in the dephosphorylated nuclear form of Yap are apparent throughout the exo-crine compartment and correlate with increases in levels of cell proliferation. However, the mutant exocrine tissue displays ex-tensive disorganization leading to pancreatitis-like autodigestion. Interestingly, our results suggest that Hippo signaling does not directly regulate the pancreas endocrine compartment as Yap expression is lost following endocrine specification through a Hippo-independent mechanism. Altogether, our results demonstrate that Hippo signaling plays a crucial role in pancreas devel-opment and provide novel routes to a better understanding of pathological conditions that affect this organ. First identified inDrosophila andhighly conserved inmammals,the Hippo pathway consists of a series of kinases thought to be regulated by cell-cell contact (7, 19, 33). This pathway is activated by undefined signals most likely emanating from the cell surface, which leads to activation of the redundant mammalian Ste20-lik