title: Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development.
abstract: 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.
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Urness
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bleyl
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Wright
authors.forename: Anne M
authors.initials: AM
authors.lastname: Moon
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Mansour
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000502:physiology*; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000502:physiology*; D051518:Fibroblast Growth Factor 3 / Q000502:physiology*; D051524:Fibroblast Growth Factor 8 / Q000235:genetics; D006321:Heart / Q000196:embryology*; D051379:Mice; D018919:Neovascularization, Physiologic; D009432:Neural Crest / Q000002:abnormalities; D011247:Pregnancy; D020825:T-Box Domain Proteins / Q000235:genetics
chemical_list: C496464:Fgf10 protein, mouse; C489197:Fgf3 protein, mouse; C496457:Fgf8 protein, mouse; D051526:Fibroblast Growth Factor 10; D051518:Fibroblast Growth Factor 3; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D051524:Fibroblast Growth Factor 8