Journal
GASTROENTEROLOGY
Volume 144, Issue 7, Pages 1543-U380Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2013.02.037
Keywords
Mouse Model; Signal Transduction; Hpo; Wts
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Funding
- NCI NIH HHS [R01 CA133557, K99 CA158582, R01 CA136567, P30 CA016520] Funding Source: Medline
- NIDDK NIH HHS [P30-DK050306, R01 DK083355, DK083111, DP2 DK083111, P30 DK040561, P30 DK043351, P30 DK050306, T32 DK007066] Funding Source: Medline
- PHS HHS [GSE35004] Funding Source: Medline
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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 chemicalinduced pancreatitis in mice. CONCLUSIONS: The mammalian Hippo kinases, and YAP, maintain postnatal pancreatic acinar differentiation in mice.
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