Abstract
ABSTRACTDevelopmental 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. 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. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant 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. 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. 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.
Highlights
Conotruncal heart malformations, which affect the outflow tract and aortic arch arteries, occur in 30% of all cases of congenital heart defects (Thom et al, 2006)
Of the genes deleted in 22q11 deletion syndrome (22q11DS), hemizygosity of TBX1 is considered to be the cause of the cardiovascular defects, with point mutations in TBX1 identified in individuals with 22q11DS-like phenotypes (Yagi et al, 2003; Zweier et al, 2007)
Loss of Pax9 results in complex cardiovascular defects Pax9 plays a key role in cardiovascular development, as Pax9–/– neonates and embryos display a range of cardiovascular defects
Summary
Conotruncal heart malformations, which affect the outflow tract and aortic arch arteries, occur in 30% of all cases of congenital heart defects (Thom et al, 2006). Several genes have been identified as potential modifiers of 22q11DS, as determined by genetic interaction studies and transcriptome analyses in Tbx mutant mice (Aggarwal and Morrow, 2008; Ivins et al, 2005; Liao et al, 2008; Papangeli and Scambler, 2013). One such candidate gene is Pax the expression of which in the pharyngeal endoderm was found to be significantly reduced in Tbx1-deficient embryos (Ivins et al, 2005; Liao et al, 2008). Embryos deficient for Pax exhibit craniofacial defects, including a cleft secondary palate as well as absent teeth, skeletal defects and lack derivatives of the 3rd and 4th pharyngeal pouches, i.e. the thymus, parathyroids and ultimobranchial bodies (Peters et al, 1998), yet the role of Pax in cardiovascular development has not been determined
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