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.

Genetics and Genomics of Congenital Heart Disease

“…Notch signaling is a highly conserved pathway mediating local intercellular communication that has important roles in a host of developmental processes that are very relevant to heart development, including formation of the left-right organizer 89 , blood vessel development 90 and ventricular chamber development 91 . Notch signaling provides a way for a Notch ligand from one cell to influence a directly neighboring cell via its Notch receptor (Fig.…”

Histone demethylases Kdm6ba and Kdm6bb redundantly promote cardiomyocyte proliferation during zebrafish heart ventricle maturation

“…These specialized trabeculating cardiomyocytes then clonally expand during early larval stages to form extensive ridge-like cardiac trabeculae that protrude into the ventricular cavity. The initial phase of trabeculation driven by neuregulin/ErbB2 signaling (Han et al, 2016; Liu et al, 2010; Peshkovsky et al, 2011) does not depend on Kdm6b as we saw that small groups of multiple cell layer thick myocardium still form in kdm6b -deficient fish. Instead, Kdm6b is required for the subsequent boost of proliferation at larval hatching (around 96 hpf) seen in trabeculating myocardial cells (Gupta and Poss, 2012; Han et al, 2016; Liu et al, 2010) as well as adjacent endocardium that concomitantly expands to enshroud the forming trabeculae.…”

“…Trabeculation of the zebrafish ventricle initiates around 72 hpf with the specification of a small number of trabeculating cardiomyocytes that separate from the otherwise single cell-thick outer myocardial layer (Gupta and Poss, 2012; Han et al, 2016; Liu et al, 2010; Peshkovsky et al, 2011). These specialized trabeculating cardiomyocytes then clonally expand during early larval stages to form extensive ridge-like cardiac trabeculae that protrude into the ventricular cavity.…”

Mechanisms of Trabecular Formation and Specification During Cardiogenesis

“…3). These studies show that the trabecular morphogenesis in the mouse is different from zebrafish, in which trabeculae are initiated by directional migration but not OCD 28,29 . Whether OCD and directional migration contribute to trabecular morphogenesis needs further study, which will be discussed below.…”