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

View ORCID ProfileHelen M. Phillips, Catherine A. Stothard, Wasay Mohiuddin Shaikh Qureshi, Anastasia I. Kousa, J. Alberto Briones-Leon, Ramada R. Khasawneh, Rachel Sanders, Silvia Mazzotta, Rebecca Dodds, Kerstin Seidel, Timothy Bates, Mitsushiro Nakatomi, View ORCID ProfileSimon J. Cockell, View ORCID ProfileJürgen E. Schneider, Timothy J. Mohun, View ORCID ProfileRené Maehr, View ORCID ProfileRalf Kist, View ORCID ProfileHeiko Peters, View ORCID ProfileSimon D. Bamforth
doi: https://doi.org/10.1101/576660
Helen M. Phillips
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
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  • ORCID record for Helen M. Phillips
Catherine A. Stothard
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
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Wasay Mohiuddin Shaikh Qureshi
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
8School of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK
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Anastasia I. Kousa
2Memorial Sloan Kettering Cancer Center, NY 10065, USA
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J. Alberto Briones-Leon
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
9Cambridge Healthcare Research, Cambridge, CB4 0WS, UK
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Ramada R. Khasawneh
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
10Yarmouk University, Irbid, Jordan
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Rachel Sanders
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
11The Queen’s Medical Research Institute, University of Edinburgh, EH16 4TJ, UK
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Silvia Mazzotta
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
12TC BioPharm Limited, Motherwell, ML1 4WR, UK
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Rebecca Dodds
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
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Kerstin Seidel
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
13Genentech Inc., South San Francisco, CA 94080, USA
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Timothy Bates
3School of Dental Sciences, Newcastle University, Newcastle-upon-Tyne, NE2 4BW, UK
14Queen Elizabeth Hospital, Birmingham, B15 2GW, UK
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Mitsushiro Nakatomi
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
15Kyushu Dental University, Kitakyushu, 803-8580, Japan
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Simon J. Cockell
4Bioinformatics Support Unit, Newcastle University, Newcastle-upon-Tyne, NE2 4HH, UK
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Jürgen E. Schneider
5Biomedical Imaging, University of Leeds, Leeds, LS2 9JT, UK
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Timothy J. Mohun
6The Francis Crick Institute, London, NW1 1AT, UK
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René Maehr
7Diabetes Center of Excellence, University of Massachusetts Medical School, MA 01605, USA
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Ralf Kist
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
3School of Dental Sciences, Newcastle University, Newcastle-upon-Tyne, NE2 4BW, UK
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Heiko Peters
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
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Simon D. Bamforth
1Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK
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  • For correspondence: simon.bamforth@newcastle.ac.uk
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Abstract

Developmental defects affecting the heart and aortic arch arteries are a key phenotype observed in DiGeorge syndrome patients and are caused by a microdeletion on chromosome 22q11. Heterozygosity of TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key component 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 affecting 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 to Tbx1 heterozygous mice. Using a novel Pax9Cre allele we demonstrated that the site of this Tbx1-Pax9 genetic interaction is in the pharyngeal endoderm, therefore revealing that a Tbx1/Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for critical tissue interactions during normal morphogenesis of the pharyngeal arch artery system.

Summary statement Pax9 is required for outflow tract and aortic arch development, and functions together with Tbx1 in the pharyngeal endoderm for 4th arch artery formation.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted March 14, 2019.
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Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis
Helen M. Phillips, Catherine A. Stothard, Wasay Mohiuddin Shaikh Qureshi, Anastasia I. Kousa, J. Alberto Briones-Leon, Ramada R. Khasawneh, Rachel Sanders, Silvia Mazzotta, Rebecca Dodds, Kerstin Seidel, Timothy Bates, Mitsushiro Nakatomi, Simon J. Cockell, Jürgen E. Schneider, Timothy J. Mohun, René Maehr, Ralf Kist, Heiko Peters, Simon D. Bamforth
bioRxiv 576660; doi: https://doi.org/10.1101/576660
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Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis
Helen M. Phillips, Catherine A. Stothard, Wasay Mohiuddin Shaikh Qureshi, Anastasia I. Kousa, J. Alberto Briones-Leon, Ramada R. Khasawneh, Rachel Sanders, Silvia Mazzotta, Rebecca Dodds, Kerstin Seidel, Timothy Bates, Mitsushiro Nakatomi, Simon J. Cockell, Jürgen E. Schneider, Timothy J. Mohun, René Maehr, Ralf Kist, Heiko Peters, Simon D. Bamforth
bioRxiv 576660; doi: https://doi.org/10.1101/576660

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