Hippo signaling regulates differentiation and maintenance in the exocrine pancreas

Background & Aims: The Hippo signaling pathway is a context-dependent regulator of cell proliferation, differentiation, and apoptosis in species ranging from Drosophila to humans. In this study, we investigated the role of the core Hippo kinases - Mst1 and Mst2 - in pancreatic development and homeostasis. Methods: We used a Cre/LoxP system to create mice with pancreas-specific disruptions in Mst1 and Mst2 (Pdx1-Cre;Mst1 ^-/-;Mst2^fl/fl mice), the mammalian orthologs of Drosophila Hippo. We used a transgenic approach to overexpress Yap, the downstream mediator of Hippo signaling, in the developing pancreas of mice. Results: Contrary to expectations, the pancreatic mass of Pdx1-Cre;Mst1 ^-/-;Mst2^fl/fl mice was reduced compared with wild-type mice, largely because of postnatal de-differentiation of acinar cells into duct-like cells. Development of this phenotype coincided with postnatal reactivation of YAP expression. Ectopic expression of YAP during the secondary transition (a stage at which YAP is normally absent) blocked differentiation of the endocrine and exocrine compartments, whereas loss of a single Yap allele reduced acinar de-differentiation. The phenotype of Pdx1-Cre;Mst1 ^-/-;Mst2^fl/fl mice recapitulated cellular and molecular changes observed during chemical-induced pancreatitis in mice. Conclusions: The mammalian Hippo kinases, and YAP, maintain postnatal pancreatic acinar differentiation in mice.