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Development. 2019 Sep 23;146(18). pii: dev177618. doi: 10.1242/dev.177618.

Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis.

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Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne NE1 3BZ, UK.
Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
School of Dental Sciences, Newcastle University, Newcastle-upon-Tyne NE2 4BW, UK.
Bioinformatics Support Unit, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK.
Biomedical Imaging, University of Leeds, Leeds LS2 9JT, UK.
The Francis Crick Institute, London NW1 1AT, UK.
Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne NE1 3BZ, UK


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. 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.


22q11 deletion syndrome; Arch artery development; Neural crest; Pax9; Pharyngeal endoderm; Tbx1

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