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Kidney Week

Abstract: PO1551

Cux1 Regulates Cilia Length in Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Vanden heuvel, Greg, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, United States
  • Wee, Zhi Nee, Kalamazoo College, Kalamazoo, Michigan, United States
  • Holthaus, Conner L., Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, United States

Renal cyst development in ADPKD results from mutations in the PKD1 or PKD2 genes, which encode the proteins polycstin1 (PC1) and polycystin2 (PC2). PC1 and PC2 proteins are localized to primary cilia where they are proposed to form a receptor channel complex that detects flow transmitting a calcium-mediated signal. Primary cilia are critical to the pathogenesis of ADPKD, which is one of many ciliopathies that exhibit renal cystic disease. Cux1, a murine homolog of the Drosophila gene Cut, is a cell cycle dependent transcriptional repressor that regulates the cyclin kinase inhibitor p27. Cux1 is highly and ectopically expressed in mice carrying a collecting duct (CD) specific mutation of Pkd1 (Pkd1 knockout) and in human ADPKD cells. Mice carrying mutations in both Cux1 and Pkd1 have reduced cystic disease and an increased life span. A role for Cux1 in regulating genes involved in cilia assembly and function has recently been identified in the Galapagos cormorant, however the role of Cux1 in cilia in the mammalian kidney is not known.


To begin to determine whether Cux1 regulates ciliogenesis we evaluated cilia morphology and the expression of the ciliary protein, OFD1 (oral-facial-digital-1), identified as a Cux1 target in the Galapagos cormorant. Cilia analysis was performed on kidneys isolated from wild type, Cux1 transgenic, Pkd1 knockout, and Pkd1/Cux1 double knock out mice. Cilia morphology was assessed by immunofluorescence labeling of alpha-tubulin, a major component of cilia, and the collecting duct marker dolichos biflorus agglutinin (DBA) to identify cells in which Pkd1 was deleted.


Cilia in Pkd1/Cux1 double knockout kidneys were significantly shorter than cilia in the Pkd1 knockout kidneys alone, consistent with previous studies showing that decreased cilia length corresponds to decreased cystic disease. OFD1 is an inhibitor of ciliogenesis and OFD1 expression in the various mouse models demonstrate that OFD1 expression corresponds to Cux1 expression. OFD1 protein levels were the lowest in the kidneys of mice constitutively expressing Cux1 and were highest in mice with deletions of Cux1.


Taken together, our results suggest a novel role for Cux1 in regulating ciliogenesis in the kidney and that reduced cystic disease in the Pkd1/Cux1 double mutant mice results from reduced cilia length.