title: Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis.
abstract: OBJECTIVE
  Defects in cilia formation or function have been implicated in several human genetic diseases, including polycystic kidney disease (PKD), Bardet-Biedl syndrome, and primary ciliary dyskinesia. Pancreatic lesions are found in approximately 10% of PKD patients, suggesting a connection between cilia defects and pancreatic pathologies. Here, we investigate the role of cilia in pancreas formation and function by analyzing mice that lack cilia in pancreatic cells.
  
  
  METHODS
  Using Cre/lox technology, we conditionally inactivated Kif3a, the gene encoding for a subunit of the kinesin-2 complex that is essential for cilia formation, in pancreatic epithelia. Kif3a mice were studied by immunohistochemical and biochemical methods to assess the morphology and differentiation status of pancreatic cells.
  
  
  RESULTS
  Tissue-specific loss of Kif3a in pancreatic cells resulted in severe pancreatic abnormalities including acinar-to-ductal metaplasia, fibrosis, and lipomatosis. Ductal metaplasia appears to be due to expansion of ductal cells rather than transdifferentiation of acinar cells. Cyst formation, aberrant ductal morphology, and extensive fibrosis associated with severe adhesion to adjacent organs were commonly observed in aged Kif3a mutant mice. Deletion of Kif3a using different pancreas-specific Cre strains suggests that these pancreatic phenotypes might be caused by the absence of cilia in ductal cells. Activation of transforming growth factor beta and Mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways may play a role in these phenotypes.
  
  
  CONCLUSIONS
  These results demonstrate that the absence of cilia in pancreatic cells produces pancreatic lesions that resemble those found in patients with chronic pancreatitis or cystic fibrosis.
authors.affiliation: Diabetes Center, Department of Medicine, University of California San Francisco, California 94143, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Cano
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sekine
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
mesh_terms: D000818:Animals; D002923:Cilia / Q000235:genetics / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000648:ultrastructure; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D008068:Lipomatosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D010179:Pancreas / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010181:Pancreatic Cyst / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D010183:Pancreatic Ducts / Q000473:pathology / Q000648:ultrastructure; D010195:Pancreatitis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C490202:Kif3a protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D016547:Kinesins