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Abstract: FR-PO546

Cleavage of PC1 Is Not Required for Embryonic Vasculature Development

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic


  • Basquin, Denis, University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Outeda, Patricia, University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Watnick, Terry J., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Qian, Feng, University of Maryland School of Medicine, Baltimore, Maryland, United States

Polycystin 1 (PC1) is a large membrane protein that undergoes an autoproteolytic cleavage at a G protein coupled receptor (GPS) site. PC1 cleavage at the GPS is essential for trafficking of the PC1/PC2 complex to the primary cilium. While homozygous Pkd1 or Pkd2 knock-out mice die at mid-gestation due to vascular and lymphatic abnormalities homozygous Pkd1V/V mutant embryos, harboring a mutation that abolishes PC1 cleavage, survive embryogenesis, suggesting that uncleaved PC1 (PC1V) might play a role in embryonic vascular development.


We analyzed the vascular phenotype of Pkd1V/V, Pkd1-/- and control E14.5 embryos including placenta branching morphogenesis and epidermal lymphatic vessel development. Rescue experiments were performed using a transgenic BAC expressing HA-tagged-PC1V (PC1V-F/H). We evaluated the impact of PC1 cleavage on cell migration/polarity via wound healing assay. Trafficking of PC1V and the PC2/PC1V complex was assessed by N-glycosylation studies and biotinylation assays. Localization of PC1 and PC1V in the cilia was performed using immunofluorescence in endothelial cells (EC).


Pkd1V/V embryos lacked the vascular abnormalities observed in Pkd1-/- embryos including hemorrhage, edema and polyhydramnios. The complexity of the placental labyrinth vasculature and the lymphatic vasculature were similar between Pkd1V/V and controls but reduced in Pkd1-/- embryos. Transgenic expression of PC1V-F/H was sufficient to rescue the vascular phenotype observed in Pkd1-/- mutants. Using wound-healing assays we observed that Pkd1V/V cells migrated properly and that front-rear polarity was similar to controls. We confirmed that PC1 and PC2 colocalized in the primary cilia of cultured ECs. In contrast, PC2 was undetectable in cilia from Pkd1V/V cells. In addition, we showed that the pool of PC2 protein that co-immunoprecipitated with PC1V was Endo H sensitive, indicating that PC1 cleavage is a pre-requisite for the protein complex to traffic beyond the Golgi in ECs. PC1V was partially resistant to Endo H and able to reach the cell surface.


Our data suggests that expression and localization of PC1 and/or PC2 in the primary cilia of ECs is not required for a proper vascular/lymphatic vessel development. This is the first time that an extraciliary role for full length PC1 has been identified.


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