Abstract
Communication between neighboring tissues plays a central role in guiding organ morphogenesis. During heart tube assembly, interactions with the adjacent endoderm control the medial movement of cardiomyocytes, a process referred to as cardiac fusion. However, the molecular underpinnings of this endodermal-myocardial relationship remain unclear. Here, we show an essential role for platelet-derived growth factor receptor alpha (Pdgfra) in directing cardiac fusion. Mutation of pdgfra disrupts heart tube assembly in both zebrafish and mouse. Timelapse analysis of individual cardiomyocyte trajectories reveals misdirected cells in zebrafish pdgfra mutants, suggesting that PDGF signaling steers cardiomyocytes toward the midline during cardiac fusion. Intriguingly, the ligand pdgfaa is expressed in the endoderm medial to the pdgfra-expressing myocardial precursors. Ectopic expression of pdgfaa interferes with cardiac fusion, consistent with an instructive role for PDGF signaling. Together, these data uncover a novel mechanism through which endodermal-myocardial communication can guide the cell movements that initiate cardiac morphogenesis.
Highlights
Organogenesis relies upon the coordinated regulation of precisely defined patterns of cell movement
Our analysis revealed a range of early defects in cardiac morphogenesis in homozygous platelet-derived growth factor receptor alpha (Pdgfra) mutants at E9.5 (Figure 3A–E’; Table 5)
Our studies point to a model in which the platelet-derived growth factor (PDGF) signaling pathway facilitates communication between the endoderm and the myocardium and thereby directs cardiomyocytes toward the midline during cardiac fusion
Summary
Organogenesis relies upon the coordinated regulation of precisely defined patterns of cell movement. PDGF signaling has been shown to control the direction of mesodermal movement during gastrulation (Damm and Winklbauer, 2011; Nagel et al, 2004), suggesting that it could guide the route taken by myocardial cells during cardiac fusion To test these hypotheses, we tracked individual cell movements over time, using the myocardial reporter transgene Tg(myl7:egfp) (Holtzman et al, 2007; Huang et al, 2003) to follow the patterns of cardiomyocyte behavior in live embryos (Figure 6). In our wild-type timelapse data, almost all cardiomyocytes move in the medial direction, whereas over half of the cardiomyocytes in our ref mutant timelapse data show no medial movement, with many of these cells moving away from the midline (Figure 6L) Together, these data reveal that pdgfra plays an important role in steering cardiomyocyte movement toward the midline during cardiac fusion. The ability of ectopic pdgfaa expression to disrupt cardiac fusion indicates that PDGF signaling has the potential to serve as an instructive influence in directing cardiomyocytes toward the midline
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