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Abstract: TH-OR103

Polycystin Signaling: Control of Tubule Cell Shape by Actomyosin-Dependent Apical Constriction

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Hofherr, Alexis, Medical Center – University of Freiburg, Freiburg im Breisgau, Germany
  • Seger, Claudia, Medical Center – University of Freiburg, Freiburg im Breisgau, Germany
  • Dixon, Eryn E., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Svendsen, Samuel L.C., Aarhus University, Aarhus C, Denmark
  • Woodward, Owen M., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Leipziger, Jens G., Aarhus University, Aarhus C, Denmark
  • Kottgen, Michael, Medical Center – University of Freiburg, Freiburg im Breisgau, Germany

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal disease affecting approximately 1 in 500 adults. Mutations in two genes cause ADPKD. Polycystic kidney disease 1 (PKD1) accounts for 85 % of patients and PKD2 accounts for the remaining 15 % of patients. Elegant experiments in model organisms have uncovered that the respective proteins, Polycystin-1 (PC1) and transient receptor potential ion channel Polycystin-2 (TRPP2), form a receptor-ion channel complex which is essential for renal morphogenesis and maintenance. The molecular components, however, connecting the two ADPKD proteins to these processes have remained elusive. Or more specifically, the intracellular effectors translating PC1/TRPP2 receptor-ion channel activity into three-dimensional tissue organization connecting genetics, cellular output, and tissue mechanics are unknown.


We have addressed this issue for the kidney with an unbiased high-resolution mass spectrometry-based screen for TRPP2-binding proteins in polarized renal epithelial cells followed by targeted analyses of PC1/TRPP2 function in vitro and in vivo. In vitro analyses of PC1/TRPP2 and candidate proteins were performed using CRISPR/Cas- and TALEN-based gene-specific knock-out and knock-in Madin-Darby canine kidney (MDCK) cell models. Wild-type and mutant zebrafish, mice, and human samples were used to validate results in vivo.


Here we identify an apical junction associated multi protein signaling complex as functional PC1/TRPP2 effector and show: 1) how the PC1/TRPP2 complex controls cellular shape by actomyosin-dependent apical constriction; 2) that this cellular contraction translates on a tissue-scale into a coordinated fine-tuning of renal tubular diameter in vivo; and 3) that in human ADPKD kidneys, tubular shape is lost, because of impaired signal integration disconnecting mutant cells from their healthy surroundings.


ADPKD is a prime example for a disease affecting renal morphogenesis and maintenance. We anticipate that our detailed characterization of the various levels of polycystin-dependent renal tubular cell shape control may help to elucidate the complex cellular machinery integrating genetic, cellular, and mechanical inputs in health and renal disease.


  • NIDDK Support