GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish

Animal science

In Vivo Visualization of Cardiomyocyte Apicobasal Polarity Reveals Epithelial to Mesenchymal-like Transition during Cardiac Trabeculation

Despite great strides in understanding cardiac trabeculation, many mechanistic aspects remain unclear. To elucidate how cardiomyocyte shape changes are regulated during this process, we engineered transgenes to label their apical and basolateral membranes. Using these tools, we observed that compact-layer cardiomyocytes are clearly polarized while delaminating cardiomyocytes have lost their polarity. The apical transgene also enabled the imaging of cardiomyocyte apical constriction in real time. Furthermore, we found that Neuregulin signaling and blood flow/cardiac contractility are required for cardiomyocyte apical constriction and depolarization. Notably, we observed the activation of Notch signaling in cardiomyocytes adjacent to those undergoing apical constriction, and we showed that this activation is positively regulated by Neuregulin signaling. Inhibition of Notch signaling did not increase the percentage of cardiomyocytes undergoing apical constriction or of trabecular cardiomyocytes. These studies provide information about cardiomyocyte polarization and enhance our understanding of the complex mechanisms underlying ventricular morphogenesis and maturation

Proteolysis regulates cardiomyocyte maturation and tissue integration

Tissue integrity is critical for organ formation and function. During heart development, cardiomyocytes differentiate and integrate to form a coherent tissue that contracts synchronously. However, the molecular mechanisms regulating cardiac tissue integrity are poorly understood. Here we show that proteolysis, via the E3 ubiquitin ligase ASB2, regulates cardiomyocyte maturation and tissue integrity. Cardiomyocytes in asb2b zebrafish mutants fail to terminally differentiate, resulting in reduced cardiac contractility and output. Mosaic analyses reveal a cell-autonomous requirement for Asb2b in cardiomyocytes for their integration as asb2b mutant cardiomyocytes are unable to meld into wild-type myocardial tissue. In vitro and in vivo data indicate that ASB2 negatively regulates TCF3, a bHLH transcription factor. TCF3 must be degraded for cardiomyocyte maturation, as TCF3 gain-of-function causes a number of phenotypes associated with cardiomyocyte dedifferentiation. Overall, our results show that proteolysis has an important role in cardiomyocyte maturation and the formation of a coherent myocardial tissue