Biology subjects

Piesker, J.

Publications and source records attributed to Piesker, J..

4 recordsLinked to original sources

bioRxiv2020

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 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.

developmental biology↗

bioRxiv2020

Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish

Mammalian models have been instrumental to investigate adult heart function and human disease. However, electrophysiological differences with human hearts and high costs emphasize the need for additional models. The zebrafish is a well-established genetic model to study cardiac development and function; however, analysis of cardiac phenotypes in adult specimens is particularly challenging as they are opaque. Here, we optimized and combined multiple imaging techniques including echocardiography, magnetic resonance imaging and micro-computed tomography to identify and analyze cardiac phenotypes in adult zebrafish. Using alk5a/tgfbr1a mutants as a case study, we observed morphological and functional cardiac defects, which were undetected with conventional approaches. Correlation analysis of multiple parameters revealed an association between hemodynamic defects and structural alterations of the heart, as observed clinically. Thus, we report a comprehensive and sensitive platform to identify otherwise indiscernible cardiac phenotypes in adult zebrafish, a model with clear advantages to study cardiac function and disease.

developmental biology↗

bioRxiv2020

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

The development of the cardiac outflow tract (OFT), which connects the heart to the great arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) cells. Defects in OFT development can lead to severe malformations, including aortic aneurysms, which have often been associated with impaired TGF-{beta} signaling. To further investigate the role of TGF-{beta} signaling in OFT formation, we generated zebrafish lacking the type I TGF-{beta} receptor Alk5 and found a strikingly specific dilation of the OFT. alk5 mutants also exhibit increased EC numbers, extracellular matrix (ECM) and SMC disorganization. Surprisingly, endothelial-specific alk5 overexpression in alk5 mutants rescues both endothelial and SMC defects. Furthermore, modulation of the ECM gene fibulin-5, a TGF-{beta} target, partially restores OFT morphology and function. These findings reveal a new requirement for endothelial TGF-{beta} signaling in OFT morphogenesis and suggest an important role for the endothelium in the etiology of aortic malformations.

developmental biology↗

bioRxiv2019

Cardiac valve regeneration in adult zebrafish: importance of TGF-β signaling in new tissue formation

Cardiac valve disease can lead to severe cardiac dysfunction and is thus a frequent cause of morbidity and mortality. Its main treatment is valve replacement, which is currently greatly limited by the poor recellularization and tissue formation potential of the implanted valves. As we still lack suitable animal models to identify modulators of these processes, here we used the adult zebrafish and found that, upon valve decellularization, they initiate a striking regenerative program that leads to the formation of new functional valves. After injury, endothelial and kidney marrow-derived cells undergo cell cycle re-entry and differentiate into new extracellular matrix-secreting valve cells. The Transforming Growth Factor beta (TGF{beta}) signaling pathway promotes this process by enhancing progenitor cell proliferation as well as valve cell differentiation. These findings reveal a key role for TGF{beta} signaling in valve regeneration and also establish the zebrafish as a model to identify and test factors promoting valve recellularization and growth.

developmental biology↗