Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells

Surya M. Nauli, Francis J. Alenghat, Ying Luo, Eric Williams, Peter Vassilev, Xiaogang Li, Andrew E.H. Elia, Weining Lu, Edward M. Brown, Stephen J. Quinn, Donald E. Ingber, Jing Zhou

Research output: Contribution to journalArticle

1443 Scopus citations

Abstract

Several proteins implicated in the pathogenesis of polycystic kidney disease (PKD) localize to cilia. Furthermore, cilia are malformed in mice with PKD with mutations in TgN737Rpw (encoding polaris). It is not known, however, whether ciliary dysfunction occurs or is relevant to cyst formation in PKD. Here, we show that polycystin-1 (PC1) and polycystin-2 (PC2), proteins respectively encoded by Pkdl and Pkd2, mouse orthologs of genes mutated in human autosomal dominant PKD, co-distribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lack functional PC1 formed cilia but did not increase Ca2+ influx in response to physiological fluid flow. Blocking antibodies directed against PC2 similarly abolished the flow response in wild-type cells as did inhibitors of the ryanodine receptor, whereas inhibitors of G-proteins, phospholipase C and InsP3 receptors had no effect. These data suggest that PC1 and PC2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of PC1 or PC2 may therefore lead to PKD owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis.

Original languageEnglish (US)
Pages (from-to)129-137
Number of pages9
JournalNature Genetics
Volume33
Issue number2
DOIs
StatePublished - Feb 1 2003

ASJC Scopus subject areas

  • Genetics

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    Nauli, S. M., Alenghat, F. J., Luo, Y., Williams, E., Vassilev, P., Li, X., Elia, A. E. H., Lu, W., Brown, E. M., Quinn, S. J., Ingber, D. E., & Zhou, J. (2003). Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature Genetics, 33(2), 129-137. https://doi.org/10.1038/ng1076