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Nauli, SM, Alenghat, FJ, Luo, Y, Williams, E, Vassilev, P, Li, X, Elia, AE, Lu, W, Brown, EM, Quinn, SJ, Ingber, DE and Zhou, J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33:129-37


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 Ca(2+) 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 InsP(3) 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.


PubMed Online version:10.1038/ng1076


Animals; Caffeine/pharmacology; Calcium/metabolism; Calcium Channels/physiology; Cilia/physiology; Epithelium/metabolism; GTP-Binding Proteins/metabolism; Heterozygote; Homeostasis/physiology; Humans; Kidney/metabolism; Membrane Proteins/physiology; Mice; Mice, Knockout; Mutation; Polycystic Kidney, Autosomal Dominant/physiopathology; Protein Binding; Protein Transport; Proteins/physiology; Ryanodine Receptor Calcium Release Channel/metabolism; Signal Transduction/physiology; TRPP Cation Channels; Tubulin/metabolism



Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status

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