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bioRxiv · 10.1101/2020.12.15.422833

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

Gentile, A.·Bensimon-Brito, A. Y. R.·Priya, R.·Maischein, H.-M.·Piesker, J.·Guenther, S.·Gunawan, F.·Stainier, D.
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Abstract

The zinc finger transcription factor Snai1 is a well-known regulator of epithelial-to-mesenchymal transition (EMT)1, 2; it is required for mesoderm ingression in flies3 and neural crest delamination in vertebrates4. During cardiac development, Snai1-regulated EMT is necessary for myocardial precursor migration and valve formation5, 6. However, a role for Snai1 in maturing cardiomyocytes (CMs) has not been reported. Here, using genetic, transcriptomic and chimeric analyses in zebrafish, we find that Snai1b is required for myocardial wall integrity. Global loss of snai1b leads to the extrusion of CMs away from the cardiac lumen, a process we show is dependent on cardiac contractility. Examining CM junctions in snai1b mutants, we observed that N-cadherin localization was compromised, thereby likely weakening cell-cell adhesion. In addition, extruding CMs exhibit increased actomyosin contractility basally, as revealed by the specific enrichment of canonical markers of actomyosin tension - phosphorylated myosin light chain (active myosin) and the -catenin epitope -18. By comparing the transcriptome of wild-type and snai1b mutant hearts at early stages of CM extrusion, we found the dysregulation of intermediate filament genes in mutants including the upregulation of desmin b. We tested the role of desmin b in myocardial wall integrity and found that CM-specific desmin b overexpression led to CM extrusion, recapitulating the snai1b mutant phenotype. Altogether, these results indicate that Snai1 is a critical regulator of intermediate filament gene expression in CMs, and that it maintains the integrity of the myocardial epithelium during embryogenesis, at least in part by repressing desmin b expression.

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Gentile, A., Bensimon-Brito, A. Y. R., Priya, R., Maischein, H.-M., Piesker, J., Guenther, S., Gunawan, F., Stainier, D.. 2020-12-16. The EMT transcription factor Snai1 maintains myocardial wall integrity by repressing intermediate filament gene expression. https://doi.org/10.1101/2020.12.15.422833

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