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Kidney Week

Abstract: FR-OR003

The Polycystin Complex Is Essential for Cilia Disassembly

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Gerakopoulos, Vasileios, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Ngo, Peter, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Tsiokas, Leonidas, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease, attributed almost exclusively to mutations in two genes, PKD1 and PKD2, encoding a receptor-channel complex (Polycystins or PKD1/PKD2) at the cell surface and the primary cilium. However, how mutations in PKD1 and/or PKD2 contribute to cyst formation/progression is unknown. The primary cilium is an antenna-like organelle present in every cell, and excessive ciliary signaling has been linked to cyst progression in ADPKD. A unique feature of the primary cilium is that it is formed when cells exit the cell cycle and disassembled upon cell cycle re-entry. Moreover, acceleration or deceleration of cilia disassembly suppresses or exaggerates cystic growth, respectively. Here, we examined whether the Polycystin complex has an essential role in cilia assembly and disassembly.


Mice Ubc-CreERT2;Pkd1f/f and Pkd1f/f mice were induced by 4-Hydroxytamoxifen from P2-P6 and sacrificed at P21. Immunofluorescence Cilia or cells in S phase were labeled with an Arl13b antibody (1:500, Proteintech) or EdU (ThermoFisher), respectively. Signaling pathways Activity of signaling pathways was determined by the Cignal 45-pathway Reporter Array (Qiagen).


Mouse embryonic fibroblasts, NIH3T3, or mouse inner medullary collecting duct (mIMCD3) cells lacking PKD1 or PKD2 showed severely delayed ciliary disassembly, whereas ciliary assembly was unaffected. These effects were specific to the deletion of Pkd1 or Pkd2 genes, as adding back wild type PKD1 or PKD2, but not pathogenic mutants, normalized ciliary disassembly. Consistently, the number of ciliated cells positive for EdU, an indicator of G1-S transition, was increased in mutant cells in cell culture and in the cystic epithelium of mice lacking Pkd1. An important intermediary was p53, which was induced in Pkd1 mutant cells and kidneys and downregulation or inhibition of p53 restored delayed disassembly in Pkd1/2-null NIH3T3 cells. Consistent with delayed disassembly in Pkd1/2-null cells, several cilia-based pathways including the TGFβ/Smad pathway, which is causally linked to cyst progression, were overactivated in mutant cells.


Our studies identify an essential role of Polycystins in cilia disassembly. Delayed disassembly in cells lacking Polycystins leads to prolonged/excessive activation of ciliary pathways that could contribute to ADPKD progression.


  • NIDDK Support