Cux1 regulates cilia length in polycystic kidney disease

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common inherited disorders affecting the kidney. Renal cyst development in ADPKD results from mutations in the PKD1 or PKD2 genes, which encode the proteins polycstin1 (PC1) and polycystin2 (PC2), respectively. 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 expression of the cyclin kinase inhibitor p27. Cux1 is highly and ectopically expressed in mice carrying a collecting duct specific mutation of Pkd1 (Pkd1CD) and in human ADPKD cells where it promotes cell proliferation. 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 target of Cux1 in the Galapagos cormorant. Cilia analysis was performed on kidneys isolated from wild type, Cux1 transgenic, Pkd1CD, and Pkd1CD/Cux1 double mutant mice. Cilia morphology was assessed by immunofluorescence labeling of alpha‐tubulin 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 Pkd1CD kidneys, 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 reveal a novel role for Cux1 in regulating ciliogenesis in the kidney and suggest that the reduced cystic disease in the Pkd1/Cux1 double mutant mice results from reduced cilia length.Support or Funding InformationAmerican Association of Anatomy FGAP, Western Michigan University Homer Stryker MD School of Medicine