Nature Genetics
37, 537 - 543 (2005)
Published online: 24 April 2005; | doi:10.1038/ng1552
Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathwaysMatias Simons1, 6, Joachim Gloy1, 6, Athina Ganner1, Axel Bullerkotte1, Mikhail Bashkurov1, Corinna Krönig1, Bernhard Schermer1, Thomas Benzing1, Olga A Cabello2, Andreas Jenny3, Marek Mlodzik3, Bozena Polok4, Wolfgang Driever4, Tomoko Obara5
& Gerd Walz11
Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany. 2
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Suite 125A, Houston, Texas 77030, USA. 3
Brookdale Department of Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA. 4
Department of Biology, University of Freiburg, Hauptstrasse 1, 79104 Freiburg, Germany. 5
Department of Medicine, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, Ohio 44109, USA. 6
These authors contributed equally to this work.
Correspondence should be addressed to Gerd Walz gerd.walz@uniklinik-freiburg.deCystic renal diseases are caused by mutations of proteins that share a unique subcellular localization: the primary cilium of tubular epithelial cells1. Mutations of the ciliary protein inversin cause nephronophthisis type II, an autosomal recessive cystic kidney disease characterized by extensive renal cysts, situs inversus and renal failure2. Here we report that inversin acts as a molecular switch between different Wnt signaling cascades. Inversin inhibits the canonical Wnt pathway by targeting cytoplasmic dishevelled (Dsh or Dvl1) for degradation; concomitantly, it is required for convergent extension movements in gastrulating Xenopus laevis embryos and elongation of animal cap explants, both regulated by noncanonical Wnt signaling. In zebrafish, the structurally related switch molecule diversin ameliorates renal cysts caused by the depletion of inversin, implying that an inhibition of canonical Wnt signaling is required for normal renal development. Fluid flow increases inversin levels in ciliated tubular epithelial cells and seems to regulate this crucial switch between Wnt signaling pathways during renal development.
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