(Q) Pax9 –/– embryos ( n=5) have bicuspid aortic valve (BAV). (P) Pax9 +/– control embryos have three normal aortic valve leaflets ( n=6): the right (RC), left (LC) and non-coronary (NC). (M-O) The ascending aorta is significantly smaller in Pax9 –/– embryos ( n=5) compared with Pax9 +/– control embryos ( n=7). (J-L) In Pax9 –/–embryos ( n=15), defects seen are DORV with interventricular communication (IVC), IAA (type B or C), A-RSA (retro-esophageal in J,K and isolated in L) and aberrant carotid arteries. (I) Pax9 +/+ embryo with normal aortic arch arteries. (I-L) 3D reconstructions of E15.5 hearts from MRI datasets. More cranially, the thymus is absent and aberrant internal and external carotid arteries (iRCA, eRCA, iLCA, eLCA) are seen (H). Hypoplastic aorta, IAA-B and an A-RSA are present (G). (F-H) In Pax9 –/–embryos ( n=4), the aorta (Ao) arises aberrantly from the right ventricle producing a double outlet right ventricle (DORV F). (C-E) Pax9 +/+ embryos at E14.5 show normal outflow tract, arch arteries and thymus. (B) Pax9 –/– neonates ( n=5) displayed IAA-B, absent right subclavian artery (presumed retro-oesophageal), and atypical right and left carotid arteries (LC and RC). (A) Arch arteries of control neonates were normal ( n=8). Loss of Pax9 results in cardiovascular developmental defects. Published by The Company of Biologists Ltd. Using a novel Pax9Cre allele, we demonstrated that the site of this Tbx1-Pax9 genetic interaction is the pharyngeal endoderm, therefore revealing that a Tbx1- Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for crucial tissue interactions during normal morphogenesis of the pharyngeal arch artery system.Ģ2q11 deletion syndrome Arch artery development Neural crest Pax9 Pharyngeal endoderm Tbx1. Transcriptome analysis indicated that Pax9 and Tbx1 may function together, and mice double heterozygous for Tbx1/ Pax9 presented with a significantly increased incidence of interrupted aortic arch when compared with Tbx1 heterozygous mice. We show here that Pax9-deficient mice are born with complex cardiovascular malformations that affect the outflow tract and aortic arch arteries with failure of the 3rd and 4th pharyngeal arch arteries to form correctly. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant mice. TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key gene, when mutated, for the arch artery defects. Developmental defects affecting the heart and aortic arch arteries are a significant phenotype observed in individuals with 22q11 deletion syndrome and are caused by a microdeletion on chromosome 22q11.
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