title: Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways.
abstract: Cystic renal diseases are caused by mutations of proteins that share a unique subcellular localization: the primary cilium of tubular epithelial cells. 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 failure. 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.
authors.affiliation: Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
authors.forename: Matias
authors.initials: M
authors.lastname: Simons
authors.forename: Joachim
authors.initials: J
authors.lastname: Gloy
authors.forename: Athina
authors.initials: A
authors.lastname: Ganner
authors.forename: Axel
authors.initials: A
authors.lastname: Bullerkotte
authors.forename: Mikhail
authors.initials: M
authors.lastname: Bashkurov
authors.forename: Corinna
authors.initials: C
authors.lastname: Krönig
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Olga A
authors.initials: OA
authors.lastname: Cabello
authors.forename: Andreas
authors.initials: A
authors.lastname: Jenny
authors.forename: Marek
authors.initials: M
authors.lastname: Mlodzik
authors.forename: Bozena
authors.initials: B
authors.lastname: Polok
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Driever
authors.forename: Tomoko
authors.initials: T
authors.lastname: Obara
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000072261:Dishevelled Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins; D029867:Xenopus Proteins; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606586:DVL1 protein, Xenopus; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; C114503:INVS protein, human; D036341:Intercellular Signaling Peptides and Proteins; C491947:Invs protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins