orpkmouse model of polycystic kidney disease reveals essential role of primary cilia in pancreatic tissue organization

Abstract

Polycystic kidney disease (PKD) includes a group of disorders that are characterized by the presence of cysts in the kidney and other organs,including the pancreas. Here we show that in orpk mice, a model system for PKD that harbors a mutation in the gene that encodes the polaris protein, pancreatic defects start to occur at the end of gestation, with an initial expansion of the developing pancreatic ducts. Ductal dilation continues rapidly after birth and results in the formation of large,interconnected cysts. Expansion of pancreatic ducts is accompanied by apoptosis of neighboring acinar cells, whereas endocrine cell differentiation and islet formation appears to be unaffected. Polaris has been shown to co-localize with primary cilia, and these structures have been implicated in the formation of renal cysts. In the orpk pancreas, cilia numbers are reduced and cilia length is decreased. Expression of polycystin-2, a protein involved in PKD, is mislocalized in orpk mice. Furthermore, the cellular localization of β-catenin, a protein involved in cell adhesion and Wnt signaling, is altered. Thus, polaris and primary cilia function are required for the maturation and maintenance of proper tissue organization in the pancreas.

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

“…58 Here we analyze the association between pancreatic pathology and cilia defects. Our findings with regards to the exocrine pancreatic defects are similar to that recently reported by Cano et al 59 The pathology includes cystic structures in the ducts, severe acinar cell apoptosis, acinar cell vacuolization with increased amylase release, abnormal intrapancreatic activation of carboxypeptidase, and elevated proliferation of the ductal epithelium associated with increased b-catenin expression. The phenotype is associated with defects in cilia on cells of the ducts and islets; however, the acinar cells were found not to have a cilium in either wildtype or mutant samples.…”

“…59 At postnatal day 1, the overall size of the pancreas from mutant and wildtype embryos appears overtly similar when compared to the size of the liver, spleen, and body weight (Figure 1a, outlined). In contrast, the size of the pancreas in postnatal day 14 mutants (Figure 1b, outlined) is dramatically reduced relative to ageand sex-matched controls.…”

“…59 While the differentiation and distribution of the cell types in the islets of Tg737 orpk mutants appear normal, the mutants have reduced blood glucose after short-term fasting and have abnormalities in glucose homeostasis after a subsequent glucose challenge relative to wild-type controls. Since recent data have implicated IFT in the hedgehog signaling pathway and hedgehog activity is known to be important in the regulation of insulin production and secretion, 55,57 the results suggest that IFT or cilia may play a role in sensing and/or regulating blood glucose levels in mice.…”

Cilium-generated signaling and cilia-related disorders

“…[53][54][55] Patients with ADPKD and ARPKD frequently have cysts in the liver and the pancreas. 52,56 Familial nephronophthisis occurs as several types, appears in juveniles, adolescents, and infants, and is characterized by shrunken kidneys and renal cysts. 57 To date, the following four nephronophthisis genes have been identified: NPHP1, which encodes nephrocystin; 58,59 NPHP2, which encodes inversin; 60 NPHP3, encoding nephrocystin 3; 61 and NPHP4 encoding nephrocystin 4 or nephroretinin.…”

The primary cilium as a gravitational force transducer and a regulator of transcriptional noise

“…Tg737, the gene mutated in the orpk mouse model of PKD, encodes polaris, a protein required for proper ciliary assembly (Pazour et al, 2000;Taulman et al, 2001;Yoder et al, 2002b). There is an increase in ␤-catenin expression and localization to dilated ducts in pancreas and increased expression levels of WNT signaling transcription factors (Cano et al, 2004) in the Tg737 mouse.…”