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The Hippo pathway effector Wwtr1 regulates cardiac wall maturation in zebrafish.

Authors
  • Lai, Jason K H1
  • Collins, Michelle M1
  • Uribe, Veronica1
  • Jiménez-Amilburu, Vanesa1
  • Günther, Stefan2
  • Maischein, Hans-Martin1
  • Stainier, Didier Y R3
  • 1 Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim 61231, Germany. , (Germany)
  • 2 Max Planck Institute for Heart and Lung Research, ECCPS Bioinformatics and Deep Sequencing Platform, Bad Nauheim 61231, Germany. , (Germany)
  • 3 Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim 61231, Germany [email protected] , (Germany)
Type
Published Article
Journal
Development
Publisher
The Company of Biologists
Publication Date
May 17, 2018
Volume
145
Issue
10
Identifiers
DOI: 10.1242/dev.159210
PMID: 29773645
Source
Medline
Keywords
License
Unknown

Abstract

Cardiac trabeculation is a highly regulated process that starts with the delamination of compact layer cardiomyocytes. The Hippo signaling pathway has been implicated in cardiac development but many questions remain. We have investigated the role of Wwtr1, a nuclear effector of the Hippo pathway, in zebrafish and find that its loss leads to reduced cardiac trabeculation. However, in mosaic animals, wwtr1-/- cardiomyocytes contribute more frequently than wwtr1+/- cardiomyocytes to the trabecular layer of wild-type hearts. To investigate this paradox, we examined the myocardial wall at early stages and found that compact layer cardiomyocytes in wwtr1-/- hearts exhibit disorganized cortical actin structure and abnormal cell-cell junctions. Accordingly, wild-type cardiomyocytes in mosaic mutant hearts contribute less frequently to the trabecular layer than when present in mosaic wild-type hearts, indicating that wwtr1-/- hearts are not able to support trabeculation. We also found that Nrg/Erbb2 signaling, which is required for trabeculation, could promote Wwtr1 nuclear export in cardiomyocytes. Altogether, these data suggest that Wwtr1 establishes the compact wall architecture necessary for trabeculation, and that Nrg/Erbb2 signaling negatively regulates its nuclear localization and therefore its activity.

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