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

Hum Mol Genet. 2016 Nov 15;25(22):5017-5026. doi: 10.1093/hmg/ddw332.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Differentiation
  • Cilia / genetics
  • Cilia / pathology*
  • Epithelial Cells / pathology
  • Hepatocyte Nuclear Factor 6 / genetics
  • Hepatocyte Nuclear Factor 6 / metabolism*
  • Lipomatosis / genetics
  • Lipomatosis / metabolism
  • Metaplasia / genetics
  • Metaplasia / metabolism
  • Mice
  • Pancreas / pathology
  • Pancreatic Ducts / metabolism
  • Pancreatic Neoplasms / genetics
  • Pancreatitis, Chronic / genetics
  • Pancreatitis, Chronic / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*

Substances

  • Hepatocyte Nuclear Factor 6
  • Onecut1 protein, mouse
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases