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Chronic pancreatitis and lipomatosis are associated with defective function of ciliary genes in pancreatic ductal cells
- 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.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Pathology
Apoptosis
AMP-Activated Protein Kinases
Protein Serine-Threonine Kinases
Biology
Ciliopathies
Mice
03 medical and health sciences
Pancreatitis, Chronic
Pancreatic cancer
Internal medicine
Genetics
medicine
Polycystic kidney disease
Animals
Lipomatosis
Cilia
Pancreatitis, chronic
skin and connective tissue diseases
Pancreas
Molecular Biology
Genetics (clinical)
Metaplasia
Cilium
Pancreatic Ducts
Cell Differentiation
Epithelial Cells
General Medicine
medicine.disease
Pancreatic Neoplasms
Hepatocyte Nuclear Factor 6
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Pancreatitis
Intraciliary transport
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics, Vol. 25, no. 22, p. 5017-5026 (2016)
- Accession number :
- edsair.doi.dedup.....be63d2d09c85920d985c2f6adcfd6053