Nature Genetics 33, 129 - 137 (2003)
Published online: 6 January 2003; | doi:10.1038/ng1076
Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cellsSurya M. Nauli1, 4, Francis J. Alenghat2, Ying Luo1, 4, Eric Williams1, Peter Vassilev3, Xiaogang Li1, Andrew E. H. Elia1, Weining Lu1, Edward M. Brown3, Stephen J. Quinn3, Donald E. Ingber2
& Jing Zhou11
Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 4 Blackfan Circle, Boston, Massachusetts 02115, USA. 2
Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA. 3
Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Jing Zhou zhou@rics.bwh.harvard.edu 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 Pkd1 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.
|
