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Chronic pancreatitis and lipomatosis are associated with defective function of ciliary genes in pancreatic ductal cells

Authors :
Frédéric P. Lemaigre
Louis Collet
Pierfrancesco Vargiu
Carmen Guerra
Sagrario Ortega
Cécile Augereau
Patrick Jacquemin
UCL - SSS/DDUV - Institut de Duve
Source :
Human Molecular Genetics, Vol. 25, no. 22, p. 5017-5026 (2016)
Publication Year :
2016
Publisher :
Oxford University Press, 2016.

Abstract

Genetic diseases associated with defects in primary cilia are classified as ciliopathies. Pancreatic lesions and ductal cysts are found in patients with ciliopathic polycystic kidney diseases suggesting a close connection between pancreatic defects and primary cilia. Here we investigate the role of two genes whose deletion is known to cause primary cilium defects, namely Hnf6 and Lkb1, in pancreatic ductal homeostasis. We find that mice with postnatal duct-specific deletion of Hnf6 or Lkb1 show duct dilations. Cells lining dilated ducts present shorter cilia with swollen tips, suggesting defective intraciliary transport. This is associated with signs of chronic pancreatitis, namely acinar-to-ductal metaplasia, acinar proliferation and apoptosis, presence of inflammatory infiltrates, fibrosis and lipomatosis. Our data reveal a tight association between ductal ciliary defects and pancreatitis with perturbed acinar homeostasis and differentiation. Such injuries can account for the increased risk to develop pancreatic cancer in Peutz-Jeghers patients who carry LKB1 loss-of-function mutations.

Details

Database :
OpenAIRE
Journal :
Human Molecular Genetics, Vol. 25, no. 22, p. 5017-5026 (2016)
Accession number :
edsair.doi.dedup.....be63d2d09c85920d985c2f6adcfd6053