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Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in

Seng Hui Low1, Shivakumar Vasanth, Claire H Larson

  • 1Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California 93106, USA.

Developmental Cell
|January 10, 2006
PubMed

Insights

Polycystin-1 (PC1) cleavage and nuclear translocation activate STAT6-dependent gene expression. This pathway is dysregulated in autosomal-dominant polycystic kidney disease (ADPKD), leading to cyst formation.

Area of Science:

  • Cell Biology
  • Genetics
  • Nephrology

Background:

  • Primary cilia play a role in autosomal-dominant polycystic kidney disease (ADPKD) pathogenesis.
  • The precise function of polycystin-1 (PC1) in cilia and ADPKD is not fully understood.

Purpose of the Study:

  • To elucidate the function of PC1 in primary cilia.
  • To investigate the mechanism linking PC1 to gene expression and ADPKD.

Main Methods:

  • Investigated PC1 proteolytic cleavage and its tail's nuclear translocation.
  • Examined interactions between the PC1 tail, STAT6, and P100.
  • Analyzed STAT6 localization in renal epithelial cells under different fluid flow conditions.
  • Assessed levels of nuclear STAT6, P100, and PC1 tail in ADPKD cyst cells.
  • Utilized zebrafish embryos to study the effect of PC1 tail expression on cystogenesis.

Main Results:

  • PC1 undergoes cleavage, translocating its cytoplasmic tail to the nucleus.
  • The PC1 tail interacts with STAT6 and P100, enhancing STAT6-dependent gene expression.
  • STAT6 normally resides in primary cilia but translocates to the nucleus upon cessation of fluid flow.
  • Elevated nuclear STAT6, P100, and PC1 tail are observed in ADPKD cyst-lining cells.
  • Expression of the PC1 tail induces renal cyst formation in zebrafish.

Conclusions:

  • Identified a novel mechanism of primary cilia function involving PC1 in mechanotransduction and gene expression.
  • Demonstrated that this PC1-STAT6 pathway is aberrantly activated in ADPKD.
  • The findings provide new insights into ADPKD pathogenesis and potential therapeutic targets.

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