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 beta-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.
Highlights
Polycystic kidney disease (PKD) includes a group of autosomal dominant (ADPKD) and autosomal recessive (ARPKD) disorders characterized by the presence of cysts in the kidney and other organs, such as liver (50% frequency) and pancreas (10% frequency)
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)
We demonstrate that pancreatic cells in orpk mice are marked by a reduction in cilia number and aberrant cilia architecture, which suggests that the pancreatic defects are caused by improper cilia assembly
Summary
Polycystic kidney disease (PKD) includes a group of autosomal dominant (ADPKD) and autosomal recessive (ARPKD) disorders characterized by the presence of cysts in the kidney and other organs, such as liver (50% frequency) and pancreas (10% frequency) (see Calvet and Grantham, 2001; Gabow, 1993; Igarashi and Somlo, 2002; Murcia et al, 1999; Wilson, 2001). 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). Both polycystin-1 and polycystin-2, the proteins encoded by Pkd and Pkd, respectively, localize to the cilium in mouse and human kidney cells (Pazour et al, 2002; Yoder et al, 2002a). Increasing evidence points to defects in cilia assembly and function as a cause of PKD
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