Hippo signaling regulates pancreas development through inactivation of Yap.
The mammalian 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 components in the developing mouse pancreas. Unexpectedly, the pancreas from Hippo-deficient offspring was reduced in size, with defects evident throughout the organ. Increases in the dephosphorylated nuclear form of Yap are apparent throughout the exocrine compartment and correlate with increases in levels of cell proliferation. However, the mutant exocrine tissue displays extensive 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 development and provide novel routes to a better understanding of pathological conditions that affect this organ.
Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA. nmgeorge@unmc.edu
Nicholas M
NM
George
Caroline E
CE
Day
Brian P
BP
Boerner
Randy L
RL
Johnson
Nora E
NE
Sarvetnick
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017228:Hepatocyte Growth Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000196:embryology* / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D017228:Hepatocyte Growth Factor; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090742:Serine-Threonine Kinase 3; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C082332:macrophage stimulating protein; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases