Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development

Heart development requires contributions from, and coordinated signaling interactions between, several cell populations, including splanchnic and pharyngeal mesoderm, postotic neural crest and the proepicardium. Here we report that Fgf3 and Fgf10, which are expressed dynamically in and near these cardiovascular progenitors, have redundant and dosage sensitive requirements in multiple aspects of early murine cardiovascular development. Embryos with Fgf3−/+;Fgf10−/−, Fgf3−/−;Fgf10−/+ and Fgf3−/−;Fgf10−/− genotypes formed an allelic series of increasing severity with respect to embryonic survival, with double mutants dead by E11.5. Morphologic analysis of embryos with three mutant alleles at E11.5–E13.5 and double mutants at E9.5–E11.0 revealed multiple cardiovascular defects affecting the outflow tract, ventricular septum, atrioventricular cushions, ventricular myocardium, dorsal mesenchymal protrusion, pulmonary arteries, epicardium and fourth pharyngeal arch artery. Assessment of molecular markers in E8.0–E10.5 double mutants revealed abnormalities in each progenitor population, and suggests that Fgf3 and Fgf10 are not required for specification of cardiovascular progenitors, but rather for their normal developmental coordination. These results imply that coding or regulatory mutations in FGF3 or FGF10 could contribute to human congenital heart defects.

Research highlights
► Cardiovascular development is sensitive to the dosage of both Fgf3 and Fgf10.
► Fgf3/Fgf10 double mutants die of heart failure by E11.5.
► Fgf3 and Fgf10 are required for normal NC, PAA4, OFT and myocardial development.
► Fgf3 & Fgf10 are required for epicardial cell ensheathment and/or adhesion to the heart myocardium.
► Fgf3 and Fgf10 regulate critical cardiac mesoderm transcription factors.