The Apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development

Abstract

The Apelin receptor (Aplnr) is essential for heart development, controlling the early migration of cardiac progenitors. Here we demonstrate that in zebrafish Aplnr modulates Nodal/TGFβ signaling, a key pathway essential for mesendoderm induction and migration. Loss of Aplnr function leads to a reduction in Nodal target gene expression whereas activation of Aplnr by a non-peptide agonist increases the expression of these same targets. Furthermore, loss of Aplnr results in a delay in the expression of the cardiogenic transcription factors mespaa/ab. Elevating Nodal levels in aplnra/b morphant and double mutant embryos is sufficient to rescue cardiac differentiation defects. We demonstrate that loss of Aplnr attenuates the activity of a point source of Nodal ligands Squint and Cyclops in a non-cell autonomous manner. Our results favour a model in which Aplnr is required to fine-tune Nodal output, acting as a specific rheostat for the Nodal/TGFβ pathway during the earliest stages of cardiogenesis.DOI: http://dx.doi.org/10.7554/eLife.13758.001

Genome-Wide Temporal Profiling of Transcriptome and Open Chromatin of Early Cardiomyocyte Differentiation Derived From hiPSCs and hESCs

“…33, 34 Their functions in cardiac development have been rarely documented. In addition, LEF1 , Wnt family member, 8A ( WNT8A ), 35 apelin receptor ( APLNR ) 36 and DiGeorge syndrome critical region 8 (DGCR8) 37 were also had high weighted connectivity in the module 8.…”

Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts

“…Apln is expressed by the endothelial cells themselves, and, in other organs, stimulates endothelial cell migration (del Toro et al, 2010; Papangeli et al, 2016). Ela is expressed non-cell autonomously in zebrafish to stimulate cell motility and nodal signaling during early embryogenesis (Chng et al, 2013; Deshwar et al, 2016; Pauli et al, 2014; Perez-Camps et al, 2016), and to activate angioblast migration toward the midline during vasculogenesis (Helker et al, 2015). Ela also has cardioprotective functions during heart failure (Sato et al, 2017) and is important for suppressing Pre-eclampsia during pregnancy (Ho et al, 2017).…”

Modeling cellular crosstalk and organotypic vasculature development with human iPSC-derived endothelial cells and cardiomyocytes

“…A gene ontology classification analysis of the 130 genes upregulated in hiPS-ECs in both cell lines revealed activation of pathways associated with cardiovascular development, cell signaling, angiogenesis, and cell differentiation ( Figure 4A). More specifically, upregulation of general EC genes ( Figure 2D), and, interestingly, cardiac EC-specific genes 28 ( Figure 4B), as well as several genes associated with heart development [29][30][31][32][33][34] (Figure 4C), and angiogenesis [35][36][37] (Figure 4D) were observed in hiPS-ECs cultured together with hiPS-CMs. The respective data for the HEL24.3 cell line are presented in Figure V in the Data Supplement.…”

“…The most significantly induced genes by both coculture and flow included genes that are implicated in vascular homeostasis , and heart development ( Figure 8C). PRCP, APLNR, PLVAP, HAPLN1, and CD59 are important in vascular health and regeneration 33,34,36,49,50 . PLVAP is also highly expressed in adult endocardium 36 .…”

“…PLVAP is also highly expressed in adult endocardium 36 . HAPLN1 (CRLT1) has been shown to be expressed in endocardium during heart development, regulating cardiac cushion formation, and is along with APLNR, and ADAMTS9 essential during cardiac development 29,33,51 . Moreover, flow and coculture both induced downregulation of atherogenic genes, such as CAV1 35 , and oxidative stress induced genes such as PGF 52,53 and SOD2 37 ( Figure 8D).…”