The EMT transcription factor Snai1 maintains myocardial wall integrity by repressing intermediate filament gene expression.

Alessandra Gentile,Felix Gunawan,Stefan Guenther,Janett Piesker,Anabela Bensimon-Brito,Rashmi Priya,Didier Yr Stainier,Hans-Martin Maischein

doi:10.7554/elife.66143

Abstract

The transcription factor Snai1, a well-known regulator of epithelial-to-mesenchymal transition, has been implicated in early cardiac morphogenesis as well as in cardiac valve formation. However, a role for Snai1 in regulating other aspects of cardiac morphogenesis has not been reported. Using genetic, transcriptomic, and chimeric analyses in zebrafish, we find that Snai1b is required in cardiomyocytes for myocardial wall integrity. Loss of snai1b increases the frequency of cardiomyocyte extrusion away from the cardiac lumen. Extruding cardiomyocytes exhibit increased actomyosin contractility basally as revealed by enrichment of p-myosin and α-catenin epitope α-18, as well as disrupted intercellular junctions. Transcriptomic analysis of wild-type and snai1b mutant hearts revealed the dysregulation of intermediate filament genes, including desmin b (desmb) upregulation. Cardiomyocyte-specific desmb overexpression caused increased cardiomyocyte extrusion, recapitulating the snai1b mutant phenotype. Altogether, these results indicate that Snai1 maintains the integrity of the myocardial epithelium, at least in part by repressing desmb expression.

Highlights

As the contractile units of the heart, cardiomyocytes (CMs) need to maintain a cohesive tissue-level cytoskeleton to beat synchronously and withstand the high mechanical forces (Sequeira et al, 2014; Gautel and Djinovic-Carugo, 2016)
Amongst the transcription factors involved in cardiac development, we focused on Snai1 (Nieto, 2002; Nieto et al, 2016), whose orthologues regulate cytoskeletal remodelling and epithelial tissue integrity in Drosophila embryos (Martin et al, 2010; Weng and Wieschaus, 2016) and in mammalian cells in culture (Wee et al, 2020)
Upon close examination of the snai1b mutant hearts, we observed a new and surprising phenotype leading to a disruption in myocardial wall integrity: CMs extrude away from the cardiac lumen (Figure 1A–D’)

Summary

Introduction

As the contractile units of the heart, cardiomyocytes (CMs) need to maintain a cohesive tissue-level cytoskeleton to beat synchronously and withstand the high mechanical forces (Sequeira et al, 2014; Gautel and Djinovic-Carugo, 2016). Using zebrafish as a model to analyse CM cytoskeletal organization at single-cell resolution, we searched for candidate transcription factors that regulate CM cytoskeletal and tissue integrity. Amongst the transcription factors involved in cardiac development, we focused on Snai (Nieto, 2002; Nieto et al, 2016), whose orthologues regulate cytoskeletal remodelling and epithelial tissue integrity in Drosophila embryos (Martin et al, 2010; Weng and Wieschaus, 2016) and in mammalian cells in culture (Wee et al, 2020). During vertebrate heart formation, Snai has been implicated in myocardial precursor migration towards the midline (Qiao et al, 2014) and in valve formation (Tao et al, 2011), but a role in myocardial wall development, during which an epithelial-to-mesenchymal (EMT)-like process occurs (Staudt et al, 2014; Jimenez-Amilburu et al, 2016; Priya et al, 2020), has not been reported

Results

Discussion

Materials and methods

Funding Funder Max Planck Society