Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737(orpk) mutant mice

• Published in: Laboratory investigation Vol. 85; no. 1; pp. 45 - 64
• Main Authors: Zhang, Qihong, Davenport, James R, Croyle, Mandy J, Haycraft, Courtney J, Yoder, Bradley K
• Format: Journal Article
• Language: English
• Published: United States 01.01.2005
• Subjects: Animals; Animals, Newborn; Apoptosis; beta-Galactosidase - metabolism; Cell Proliferation; Cilia - ultrastructure; Disease Models, Animal; Female; Fluorescent Antibody Technique, Indirect; Glucose Tolerance Test; Islets of Langerhans - abnormalities; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Male; Mice; Mice, Mutant Strains; Mice, Transgenic; Pancreas - abnormalities; Pancreas - enzymology; Pancreas - pathology; Pancreas, Exocrine - abnormalities; Pancreas, Exocrine - metabolism; Pancreas, Exocrine - pathology; Pancreatic Ducts - abnormalities; Pancreatic Ducts - metabolism; Pancreatic Ducts - pathology; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.3700207

While relatively ignored for years as vestigial, cilia have recently become the focus of intense interest as organelles that result in severe pathologies when disrupted. Here, we further establish a connection between cilia dysfunction and disease by showing that loss of polaris (Tg737), an intraflagellar transport (IFT) protein required for ciliogenesis, causes abnormalities in the exocrine and endocrine pancreas of the Tg737(orpk) mouse. Pathology is evident late in gestation as dilatations of the pancreatic ducts that continue to expand postnatally. Shortly after birth, the acini become disorganized, undergo apoptosis, and are largely ablated in late stage pathology. In addition, serum amylase levels are elevated and carboxypeptidase is abnormally activated within the pancreas. Ultrastructural analysis reveals that the acini undergo extensive vacuolization and have numerous 'halo-granules' similar to that seen in induced models of pancreatitis resulting from duct obstruction. Intriguingly, although the acini are severely affected in Tg737(orpk) mutants, cilia and Tg737 expression are restricted to the ducts and islets and are not detected on acinar cells. Analysis of the endocrine pancreas in Tg737(orpk) mutants revealed normal differentiation and distribution of cell types in the islets. However, after fasting, mutant blood glucose levels are significantly lower than controls and when challenged in glucose tolerance tests, Tg737(orpk) mutants exhibited defects in glucose uptake. These findings are interesting in light of the recently proposed role for polaris, the protein encoded by the Tg737 gene, in the hedgehog pathway and hedgehog signaling in insulin production and glucose homeostasis.