PUBLICATION

Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways

Authors
Simons, M., Gloy, J., Ganner, A., Bullerkotte, A., Bashkurov, M., Kronig, C., Schermer, B., Benzing, T., Cabello, O.A., Jenny, A., Mlodzik, M., Polok, B., Driever, W., Obara, T., and Walz, G.
ID
ZDB-PUB-050427-8
Date
2005
Source
Nature Genetics   37(5): 537-543 (Journal)
Registered Authors
Driever, Wolfgang, Obara, Tomoko, Polok, Bozena
Keywords
none
MeSH Terms
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Humans
  • Intercellular Signaling Peptides and Proteins/metabolism*
  • Phosphoproteins/genetics
  • Phosphoproteins/metabolism
  • Signal Transduction/physiology*
  • Transcription Factors/genetics*
  • Transcription Factors/metabolism
  • Wnt Proteins
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed
15852005 Full text @ Nat. Genet.
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.
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Human Disease / Model
Sequence Targeting Reagents
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Mapping