Ablation of specific expression domains reveals discrete functions of ectoderm- and endoderm-derived FGF8 during cardiovascular and pharyngeal development. Development

Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States
Development (Impact Factor: 6.46). 01/2004; 130(25):6361-74. DOI: 10.1242/dev.00850
Source: PubMed


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.

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Available from: Benjamin R Arenkiel,
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    • "Well-integrated signaling programs function through transcription factors to define tissue patterning and NCC differentiation. The complex signals that govern craniofacial morphogenesis involve a number of input pathways, including Fgf, Shh, Wnt, Bmp, Pdgf, retinoic acid (RA) and endothelin signaling (Abe et al., 2008; Abzhanov and Tabin, 2004; Clouthier et al., 2003; Jiang et al., 2006; Kurihara et al., 1995; Macatee et al., 2003). Dysregulation of NCC migration, proliferation and patterning can result in craniofacial abnormalities observed in numerous human syndromes (Chai and Maxson, 2006; Jiang et al., 2006; Noden and Trainor, 2005; Clouthier et al., 2013). "
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    ABSTRACT: In this study we examine the consequences of altering Hand1 phosphoregulation in the developing neural crest cells (NCCs) of mice. Whereas Hand1 deletion in NCCs reveals a nonessential role for Hand1 in craniofacial development and embryonic survival, altering Hand1 phosphoregulation, and consequently Hand1 dimerization affinities, in NCCs results in severe mid-facial clefting and neonatal death. Hand1 phosphorylation mutants exhibit a non-cell-autonomous increase in pharyngeal arch cell death accompanied by alterations in Fgf8 and Shh pathway expression. Together, our data indicate that the extreme distal pharyngeal arch expression domain of Hand1 defines a novel bHLH-dependent activity, and that disruption of established Hand1 dimer phosphoregulation within this domain disrupts normal craniofacial patterning.
    Development 08/2014; 141(15):3050-61. DOI:10.1242/dev.107680 · 6.46 Impact Factor
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    • "Abnormalities of NOTCH signalling in the neural crest [19] or SHF can also contribute to the development of abnormal semilunar valves [17, 20]. Interestingly, inhibition of NOTCH in SHF impairs fibroblast growth factor 8 (Fgf8) signalling, which results in the development of BAV, but also in VSMC abnormalities of the great arteries [21]. Therefore, we postulate that a developmental defect of various progenitor cell lines may provide a common mechanism underlying aortic valvulopathy (BAV), as well as aortopathy. "
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    • "During the second and third stages the lens cells elongate and the curvature of the lens placode extends to a shallow arc (stage II), and then to a semicircular shape (stage III). An omega-shaped lens pit forms in the fourth stage due to the formation of hinge points (white arrowheads, Fig. 4A) that appear radially near the surface ectoderm and drive the process of lens pit closure, which occurs at stage V. Upon deletion of p120-catenin utilizing the AP2α-cre line [AP2α (Tfap2a) is expressed in structures derived from the head ectoderm and surrounding mesenchyme (Macatee et al., 2003)], the progression of lens pit invagination shows the earliest sign of malformation at stage III and the lens pit has relatively straight epithelia without curvature at the lateral margins (white lines, Fig. 4A). A comparison with Shroom3-deficient embryos demonstrates that the shape of the lens pit is similar and their lens pits similarly lack hinge points at stages IV and V (white arrows, Fig. 4A). "
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