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Fig. 4. Ablation of FGF8 in the PA ectoderm with AP2-IRESCre reveals a unique and required role for FGF8 during PA vascular development, separate from its role in glandular and outflow tract development. (A-D) Gross morphology of perinatal control and mutant embryos. (A) Fgf8^AP/N newborn control; note that in the absence of any source of Cre, embryogenesis occurs normally with only one functional, nonhypomorphic allele of Fgf8. (B) Fgf8 newborn hypomorphic mutant (Fgf8^APN/N); the decrease in Fgf8 mRNA produced by the Fgf8^APN allele cannot support normal development resulting in neonatal death, growth delay, edema, cyanosis, craniofacial malformations (red arrowhead) and cardiovascular defects. (C) Fgf8/AP2-IRESCre E18.5 mutant; note absence of the lower jaw (red arrowhead) and bulging eyes, showing that complete ablation of FGF8 in PA1 results in a much more severe craniofacial defect than FGF8 deficiency in the hypomorph (red arrowhead). (D) Fgf8/hoxa3-IRESCre newborn has normal craniofacial development because Cre is not expressed anterior to PA3. (E-I) Thoracic dissections of control and Fgf8/AP2-IRESCre mutant newborns. (E) Wild-type specimen with normal ascending aorta and left aortic arch (Ao, arrowhead), left ductus arteriosus (DA, arrowhead), right common carotid (rcc), left common carotid (lcc), right subclavian artery (rsa), left subclavian artery (lsa), trachea (tr); the right brachiocephalic artery (rbc) branches to form the rsa and rcc. (F) Normal bilobed thymus (th) in wild-type animal. (G) Removal of the thymus (see H) from an Fgf8/AP2-IRESCre mutant reveals interrupted aortic arch type B (IAAB, no transverse aortic arch, black arrowhead), a left DA and an abnormal isolated lsa. (H) The same mutant shown in G has a normal thymus. AP2-IRESCre-mediated ablation of FGF8 separates vascular from outflow tract and pharyngeal gland defects that result from global Fgf8 deficiency. (I) Fgf8/AP2-IRESCre mutant after removal of the thymus; in this case there is a right aortic arch (Ao, arrowhead) and a right DA (arrowhead). (J-L) Transverse sections of a wild-type animal showing the normal progression (slides shown from rostral to caudal) of the head and neck vessels arising from the transverse left aortic arch. (J,K) Normal junction of rbc and lcc to lsc to form the Laa. (L) Normal ascending Ao and junction of DA to descending aorta (dA). (M) Normal right and left coronary arteries (rca, lca) arising from the left and right cusps of the aortic valve. (N-S) Fgf8/AP2-IRESCre mutants have multiple vascular anomalies caused by abnormal formation of the fourth PAAs. (N) Single coronary artery with abnormal origin of lca from right cusp of aortic valve; the rca branches off this vessel in a more caudal location. (O) Circumflex right aa (circ raa) joining lsa after a retroesophageal route; the DA also joins the lsa to form a left descending Ao (not shown). (P,Q) IAAB: the ascending aorta gives rise to the junction of the rbc and lcc (see also E). The transverse aortic arch (P, arrowhead) and descending Ao (Q, arrow) are absent, resulting in an isolated lsa that only connects with the DA (Q) to form the left descending aorta (not shown); this lesion is lethal. (R,S) A different Fgf8/AP2-IRESCre mutant with right aortic arch: the lcc joins the rbc to form the transverse region of the right-sided arch (aa). A right DA, right descending aorta (dA) and an aberrant lsa are also seen in this mutant (S).

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