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

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 flies³and neural crest delamination in vertebrates⁴. During cardiac development, Snai1-regulated EMT is necessary for myocardial precursor migration and valve formation^{5, 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 ofsnai1bleads to the extrusion of CMs away from the cardiac lumen, a process we show is dependent on cardiac contractility. Examining CM junctions insnai1bmutants, 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 α-catenin epitope α-18. By comparing the transcriptome of wild-type andsnai1bmutant hearts at early stages of CM extrusion, we found the dysregulation of intermediate filament genes in mutants including the upregulation ofdesmin b. We tested the role ofdesmin bin myocardial wall integrity and found that CM-specificdesmin boverexpression led to CM extrusion, recapitulating thesnai1bmutant 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 repressingdesmin bexpression.