Inversin relays Frizzled-8 signals to promote proximal pronephros development.
Mutations of inversin cause type II nephronophthisis, an infantile autosomal recessive disease characterized by cystic kidney disease and developmental defects. Inversin regulates Wnt signaling and is required for convergent extension movements during early embryogenesis. We now show that Inversin is essential for Xenopus pronephros formation, involving two distinct and opposing forms of cell movements. Knockdown of Inversin abrogated both proximal pronephros extension and distal tubule differentiation, phenotypes similar to that of Xenopus deficient in Frizzled-8. Exogenous Inversin rescued the pronephric defects caused by lack of Frizzled-8, indicating that Inversin acts downstream of Frizzled-8 in pronephros morphogenesis. Depletion of Inversin prevents the recruitment of Dishevelled in response to Frizzled-8 and impeded the accumulation of Dishevelled at the apical membrane of tubular epithelial cells in vivo. Thus, defective tubule morphogenesis seems to contribute to the renal pathology observed in patients with nephronophthisis type II.
Renal Division, Department of Medicine, University Hospital Freiburg, 79106 Freiburg, Germany.
Soeren
S
Lienkamp
Athina
A
Ganner
Christopher
C
Boehlke
Thorsten
T
Schmidt
Sebastian J
SJ
Arnold
Tobias
T
Schäfer
Daniel
D
Romaker
Julia
J
Schuler
Sylvia
S
Hoff
Christian
C
Powelske
Annekathrin
A
Eifler
Corinna
C
Krönig
Axel
A
Bullerkotte
Roland
R
Nitschke
E Wolfgang
EW
Kuehn
Emily
E
Kim
Hans
H
Burkhardt
Thomas
T
Brox
Olaf
O
Ronneberger
Joachim
J
Gloy
Gerd
G
Walz
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000072261:Dishevelled Proteins; D005453:Fluorescence; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D009841:Oligonucleotides / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; C113865:FZD8 protein, Xenopus; D047908:Intracellular Signaling Peptides and Proteins; C555137:Invs protein, Xenopus; D009841:Oligonucleotides; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins