Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development.
Spatial organization of cells and their appendages is controlled by the planar cell polarity pathway, a signaling cascade initiated by the protocadherin Fat in Drosophila. Vertebrates express 4 Fat molecules, Fat1-4. We found that depletion of Fat1 caused cyst formation in the zebrafish pronephros. Knockdown of the PDZ domain containing the adaptor protein Scribble intensified the cyst-promoting phenotype of Fat1 depletion, suggesting that Fat1 and Scribble act in overlapping signaling cascades during zebrafish pronephros development. Supporting the genetic interaction with Fat1, Scribble recognized the PDZ-binding site of Fat1. Depletion of Yes-associated protein 1 (YAP1), a transcriptional co-activator inhibited by Hippo signaling, ameliorated the cyst formation in Fat1-deficient zebrafish, whereas Scribble inhibited the YAP1-induced cyst formation. Thus, reduced Hippo signaling and subsequent YAP1 disinhibition seem to play a role in the development of pronephric cysts after depletion of Fat1 or Scribble. We hypothesize that Hippo signaling is required for normal pronephros development in zebrafish and that Scribble is a candidate link between Fat and the Hippo signaling cascade in vertebrates.
Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
Kassiani
K
Skouloudaki
Michael
M
Puetz
Matias
M
Simons
Jean-Remy
JR
Courbard
Christopher
C
Boehlke
Björn
B
Hartleben
Christina
C
Engel
Marcus J
MJ
Moeller
Christoph
C
Englert
Frank
F
Bollig
Tobias
T
Schäfer
Haribaskar
H
Ramachandran
Marek
M
Mlodzik
Tobias B
TB
Huber
E Wolfgang
EW
Kuehn
Emily
E
Kim
Albrecht
A
Kramer-Zucker
Gerd
G
Walz
D000818:Animals; D030801:Animals, Genetically Modified; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000196:embryology* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
D015820:Cadherins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D029961:Zebrafish Proteins; C502707:scrib protein, zebrafish; C541414:stk3 protein, zebrafish; D000099317:Hippo Kinases