Abstract
During cardiac development, endocardial cells (EdCs) produce growth factors to promote myocardial morphogenesis and growth. In particular, EdCs produce neuregulin which is required for ventricular cardiomyocytes (CMs) to seed the multicellular ridges known as trabeculae. Defects in neuregulin signaling, or in endocardial sprouting toward CMs, cause hypotrabeculation. However, the mechanisms underlying endocardial sprouting remain largely unknown. Here, we first show by live imaging in zebrafish embryos that EdCs interact with CMs via dynamic membrane protrusions. After touching CMs, these protrusions remain in close contact with their target despite the vigorous cardiac contractions. Loss of the CM-derived peptide Apelin, or of the Apelin receptor, which is expressed in EdCs, leads to reduced endocardial sprouting and hypotrabeculation. Mechanistically, neuregulin signaling requires endocardial protrusions to induce extracellular signal-regulated kinase (Erk) activity in CMs and trigger their delamination. Altogether, these data show that Apelin signaling-dependent endocardial protrusions modulate CM behavior during trabeculation.
Highlights
To meet the needs of the growing embryo, the vertebrate heart has to undergo a series of complex morphogenetic events to transform from a linear tube into a mature organ
Several studies have reported that the endocardium plays an important role during cardiac trabeculation (Grego-Bessa et al, 2007; Lai et al, 2010; D'Amato et al, 2016; Rasouli and Stainier, 2017; Del Monte-Nieto et al, 2018; Qu et al, 2019)
In comparison with endothelial sprouting, little is known about the morphogenetic events underlying endocardial sprouting and their effect on cardiac morphogenesis including trabeculation
Summary
To meet the needs of the growing embryo, the vertebrate heart has to undergo a series of complex morphogenetic events to transform from a linear tube into a mature organ. It has been shown that EdCs, similar to blood endothelial cells (ECs), form sprouts, and that these sprouts are mostly oriented towards the myocardium (Del Monte-Nieto et al, 2018). Mouse and zebrafish embryos lacking the endocardium derived ligand Nrg or the ErbB receptor, which is expressed by the myocardium, fail to form trabeculae (Gassmann et al., 1995; Lee et al, 1995; Meyer and Birchmeier, 1995; Lai et al, 2010; Liu et al, 2010; Rasouli and Stainier, 2017). A novel mechanism of cell communication by active transport of signaling molecules through filopodia-like actin rich membrane protrusions, known as cytonemes, has been shown in different models including Drosophila (Ramirez-Weber and Kornberg, 1999; Roy et al, 2011; Huang et al, 2019), chick (Sanders et al, 2013), zebrafish (Stanganello et al, 2015), and mouse (Fierro-Gonzalez et al, 2013). Our results provide new insights into the role of endocardial protrusions during cardiac trabeculation
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