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Abstract: FR-PO964

Deletion of Cep164 in the Collecting Duct Causes Polycystic Kidney Disease-Like Phenotype

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Airik, Rannar, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Airik, Merlin, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Schueler, Markus, University of Erlangen, Erlangen, Germany
  • Bates, Carlton M., Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Nephronophthisis is an inherited cause of polycystic kidney disease that represents the most common cause of end-stage renal failure in the first three decades of life. Although all known genes associated with the disease phenotype localize to the cilia, the underpinning pathomechanisms remain largely unknown. We recently reported that mutations in centrosomal protein 164(CEP164) gene, cause nephronophthisis with extrarenal manifestations in humans. In order to study the function of Cep164 in mouse we generated a Cep164 transgenic mouse model.


Targeted Cep164 ES cells were obtained from KOMP and injected into blastocysts to generate the Cep164-/- mice. Collecting duct-specific deletion of Cep164 was achieved by crossing Hoxb7-Cre mice with Cep164loxP/loxP mice. Immunofluorescence staining was used to study the expression of ciliary proteins both in celture and in the kidney. Gross morphological characterization and tissue histological analysis of mutant mice was performed on E9.5 embryos, P7, P14 and P21 animals.


Whole body deletion of Cep164 resulted in mid-gestational lethality in mice. Molecular analysis revealed that the mutant animals lacked primary cilia and had impaired hedgehog signaling. To circumvent embryonic lethality, Cep164 was deleted from the kidney collecting duct using Hoxb7-Cre mice. Deletion of Cep164 abolished cilia in the collecting duct cells of Hoxb7-Cre;Cep164loxP/loxP mice. The mutant kidneys developed normally until P7, after which they underwent a rapid cyst formation in the collecting ducts, which led to widespread structural damage, kidney failure and mortality by P21. Morphological and molecular analysis demonstrated that the rapid cyst growth was caused by uncontrolled cell proliferation in the collecting duct epithelium. Treatment with cyclin-dependent kinase inhibitors mitigated the rapid cyst growth in Hoxb7-Cre;Cep164loxP/loxP mice.


Our data demonstrate that abrogation of Cep164 leads to severe developmental abnormalities in early mouse embryogensis due to defective ciliary signaling. Conditional ablation of Cep164 in the collecting duct results in massive cyst growth in postnatal kidneys, resembling the pathogenesis of autosomal polycystic kidney disease. Together, Cep164 mouse represents a novel genetic model of autosomal recessive polycystic kidney disease.


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