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First published online November 17, 2003
doi: 10.1242/10.1242/dev.00850
1 Program in Human Molecular Biology and Genetics, University of Utah School of
Medicine, Salt Lake City, UT 84112, USA
2 Childrens Health Research Center, University of Utah School of Medicine, Salt
Lake City, UT 84112, USA
3 Program in Molecular Biology, University of Utah School of Medicine, Salt Lake
City, UT 84112, USA
4 Program in Neuroscience, University of Utah School of Medicine, Salt Lake
City, UT 84112, USA
5 Department of Pediatrics, University of Utah School of Medicine, Salt Lake
City, UT 84112, USA
6 Department of Neurobiology and Anatomy, University of Utah School of Medicine,
Salt Lake City, UT 84112, USA
* Author for correspondence (e-mail: anne.moon{at}genetics.utah.edu)
Accepted 4 September 2003
Fibroblast growth factor 8 (Fgf8) is expressed in many domains of the developing embryo. Globally decreased FGF8 signaling during murine embryogenesis results in a hypomorphic phenotype with a constellation of heart, outflow tract, great vessel and pharyngeal gland defects that phenocopies human deletion 22q11 syndromes, such as DiGeorge. We postulate that these Fgf8 hypomorphic phenotypes result from disruption of local FGF8 signaling from pharyngeal arch epithelia to mesenchymal cells populating and migrating through the third and fourth pharyngeal arches.
To test our hypothesis, and to determine whether the pharyngeal ectoderm and endoderm Fgf8 expression domains have discrete functional roles, we performed conditional mutagenesis of Fgf8 using novel Crerecombinase drivers to achieve domain-specific ablation of Fgf8 gene function in the pharyngeal arch ectoderm and endoderm.
Remarkably, ablating FGF8 protein in the pharyngeal arch ectoderm causes failure of formation of the fourth pharyngeal arch artery that results in aortic arch and subclavian artery anomalies in 95% of mutants; these defects recapitulate the spectrum and frequency of vascular defects reported in Fgf8 hypomorphs. Surprisingly, no cardiac, outflow tract or glandular defects were found in ectodermal-domain mutants, indicating that ectodermally derived FGF8 has essential roles during pharyngeal arch vascular development distinct from those in cardiac, outflow tract and pharyngeal gland morphogenesis. By contrast, ablation of FGF8 in the third and fourth pharyngeal endoderm and ectoderm caused glandular defects and bicuspid aortic valve, which indicates that the FGF8 endodermal domain has discrete roles in pharyngeal and valvar development. These results support our hypotheses that local FGF8 signaling from the pharyngeal epithelia is required for pharyngeal vascular and glandular development, and that the pharyngeal ectodermal and endodermal domains of FGF8 have separate functions.
Key words: Cardiovascular development, Pharyngeal arch, FGF8, Endoderm, Heart field, Pharyngeal arch artery, Congenital heart disease, Vasculogenesis, Aortic arch, Outflow tract, Coronary artery, Thymus, Parathyroid, 22q11 deletion syndrome, DiGeorge Syndrome
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