Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development

Proc Natl Acad Sci U S A. 2009 May 26;106(21):8579-84. doi: 10.1073/pnas.0811691106. Epub 2009 May 13.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line
  • Embryo, Nonmammalian / embryology
  • Embryo, Nonmammalian / metabolism
  • Humans
  • Kidney / embryology*
  • Kidney / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • Zebrafish / embryology*
  • Zebrafish / genetics
  • Zebrafish / metabolism*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • Cadherins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Zebrafish Proteins
  • scrib protein, zebrafish
  • Protein-Serine-Threonine Kinases
  • stk3 protein, zebrafish