Nearly 40,000 infants are born each year with Congenital Heart Defects, structural abnormalities arising from aberrant asymmetric heart development. As formation of the zebrafish heart also relies upon proper asymmetric morphogenesis, we use these organisms as a model to understand the necessary signals and cellular events that underlie this process. In zebrafish, the first asymmetric event in the heart, cardiac jogging, results in the repositioning of atrial precursors to the left and anterior of ventricular precursors. The process of jogging occurs simultaneously with the conversion of a structure called the cardiac cone into a linear heart tube. We previously discovered that the Nodal signaling pathway contributes to the asymmetry of the zebrafish heart tube by increasing the velocities of cells on the left of the cardiac cone.
Microarray analysis on isolated cardiac cells reveals upregulation of regulators of the actin cytoskeleton, FGF receptors, and FGF transcriptional targets in the heart in response to Nodal during jogging. In our preliminary data, we find evidence of the convergence of the Nodal and Fibroblast Growth Factor (FGF) pathways on the actin cytoskeleton. We also find that reduction of actin polymerization or FGF signaling mimic loss of nodal: under these conditions, tube formation is disrupted and tube extension is perturbed. Time-lapse confocal microscopy reveals a significant decrease in cell migration rates in embryos in which FGFR signaling or actin polymerization is reduced. Finally, epistasis analysis suggests that FGFR signaling functions parallel to Nodal to affect cell migration. Thus, we propose that FGFR signaling acts as a general pro-migratory signal for cardiac cells and cooperates with Nodal, which exerts an asymmetric motogenic effect on cardiac precursors by acting on the cytoskeleton.