Coordinating cardiomyocyte interactions to direct ventricular chamber morphogenesis

Abstract

Many organs are composed of complex tissue walls that are structurally organized to optimize organ function. In particular, the ventricular myocardial wall of the heart is comprised of an outer compact layer that concentrically encircles the ridge-like inner trabecular layer. Although disruption in the morphogenesis of this myocardial wall can lead to various forms of congenital heart disease (CHD)1 and non-compaction cardiomyopathies2, it remains unclear how embryonic cardiomyocytes assemble to form ventricular wall layers of appropriate spatial dimensions and myocardial mass. Here, we utilize advanced genetic and imaging tools in zebrafish to reveal an interplay between myocardial Notch and Erbb2 signaling that directs the spatial allocation of myocardial cells to their proper morphologic positions in the ventricular wall. Although previous studies have shown that endocardial Notch signaling non-cell-autonomously promotes myocardial trabeculation through Erbb2 and BMP signaling3, we discover that distinct ventricular cardiomyocyte clusters exhibit myocardial Notch activity that cell-autonomously inhibits Erbb2 signaling and prevents cardiomyocyte sprouting and trabeculation. Myocardial-specific Notch inactivation leads to ventricles of reduced size and increased wall thickness due to excessive trabeculae, whereas widespread myocardial Notch activity results in ventricles of increased size with a single-cell thick wall but no trabeculae. Notably, this myocardial Notch signaling is activated non-cell-autonomously by neighboring Erbb2-activated cardiomyocytes that sprout and form nascent trabeculae. Thus, these findings support an interactive cellular feedback process that guides the assembly of cardiomyocytes to morphologically create the ventricular myocardial wall and more broadly provides insight into the cellular dynamics of how diverse cell lineages organize to create form.