title: Hippo signaling regulates differentiation and maintenance in the exocrine pancreas.
abstract: OBJECTIVE
  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.
authors: Gastroenterology Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Tao
authors: T
authors: Gao
authors: Dawang
authors: D
authors: Zhou
authors: Chenghua
authors: C
authors: Yang
authors: Tarjinder
authors: T
authors: Singh
authors: Alfredo
authors: A
authors: Penzo-Méndez
authors: Ravikanth
authors: R
authors: Maddipati
authors: Alexandros
authors: A
authors: Tzatsos
authors: Nabeel
authors: N
authors: Bardeesy
authors: Joseph
authors: J
authors: Avruch
authors: Ben Z
authors: BZ
authors: Stanger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D051379:Mice; D008822:Mice, Transgenic; D046790:Pancreas, Exocrine / Q000254:growth & development* / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C490818:Stk3 protein, mouse