The flow responsive transcription factor Klf2 is required for myocardial wall integrity by modulating Fgf signaling

Seyed Javad Rasouli; Mohamed El-Brolosy; Ayele Taddese Tsedeke; Anabela Bensimon-Brito; Parisa Ghanbari; Hans-Martin Maischein; Carsten Kuenne; Didier Y Stainier

doi:10.7554/eLife.38889

The flow responsive transcription factor Klf2 is required for myocardial wall integrity by modulating Fgf signaling

Elife. 2018 Dec 28:7:e38889. doi: 10.7554/eLife.38889.

Authors

Seyed Javad Rasouli¹, Mohamed El-Brolosy¹, Ayele Taddese Tsedeke¹, Anabela Bensimon-Brito¹, Parisa Ghanbari², Hans-Martin Maischein¹, Carsten Kuenne³, Didier Y Stainier¹

Affiliations

¹ Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
² Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
³ Bioinformatics Core Unit, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

Abstract

Complex interplay between cardiac tissues is crucial for their integrity. The flow responsive transcription factor KLF2, which is expressed in the endocardium, is vital for cardiovascular development but its exact role remains to be defined. To this end, we mutated both klf2 paralogues in zebrafish, and while single mutants exhibit no obvious phenotype, double mutants display a novel phenotype of cardiomyocyte extrusion towards the abluminal side. This extrusion requires cardiac contractility and correlates with the mislocalization of N-cadherin from the lateral to the apical side of cardiomyocytes. Transgenic rescue data show that klf2 expression in endothelium, but not myocardium, prevents this cardiomyocyte extrusion phenotype. Transcriptome analysis of klf2 mutant hearts reveals that Fgf signaling is affected, and accordingly, we find that inhibition of Fgf signaling in wild-type animals can lead to abluminal cardiomyocyte extrusion. These studies provide new insights into how Klf2 regulates cardiovascular development and specifically myocardial wall integrity.

Keywords: Fgf signaling; Klf2; cardiomyocyte behavior; cell extrusion; developmental biology; myocardial wall integrity; zebrafish; zebrafish heart development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Base Sequence
Cadherins / metabolism
Cell Death
Cell Polarity
Cell Proliferation
Down-Regulation
Embryo, Nonmammalian / metabolism
Extracellular Signal-Regulated MAP Kinases / metabolism
Fibroblast Growth Factors / metabolism*
Gene Expression Regulation, Developmental
Hedgehog Proteins / metabolism
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism*
Ligands
Mutation / genetics
Myocardial Contraction
Myocardium / cytology
Myocardium / metabolism*
Myocytes, Cardiac / cytology
Myocytes, Cardiac / metabolism
Phenotype
Phosphorylation
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Fibroblast Growth Factor / metabolism
Signal Transduction*
Tretinoin / metabolism
Zebrafish / embryology
Zebrafish / genetics
Zebrafish / metabolism
Zebrafish Proteins / genetics
Zebrafish Proteins / metabolism*

Substances

Cadherins
Hedgehog Proteins
Klf2 Protein, zebrafish
Kruppel-Like Transcription Factors
Ligands
RNA, Messenger
Receptors, Fibroblast Growth Factor
Zebrafish Proteins
Tretinoin
Fibroblast Growth Factors
Extracellular Signal-Regulated MAP Kinases

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.