TY - JOUR
T1 - Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis
AU - Phillips, Helen M.
AU - Stothard, Catherine A.
AU - Qureshi, Wasay M. Shaikh
AU - Kousa, Anastasia L.
AU - Briones-Leon, J. Alberto
AU - Khasawneh, Ramada R.
AU - O'Loughlin, Chloe
AU - Sanders, Rachel
AU - Mazzotta, Silvia
AU - Dodds, Rebecca
AU - Seidel, Kerstin
AU - Bates, Timothy C
AU - Nakatomi, Mitsushiro
AU - Cockell, Simon J.
AU - Schneider, Jurgen E.
AU - Mohun, Timothy J.
AU - Maehr, Rene'
AU - Kist, Ralf
AU - Peters, Heiko
AU - Bamforth, Simon D.
N1 - Funding
British Heart Foundation (PG/14/28/30774)
Consejo Nacional de Ciencia y Tecnología, Guatemala (NO AWARD)
Newcastle upon Tyne Hospitals NHS Foundation Trust (BH120404)
Yarmouk University (NO AWARD)
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
KW - Pharyngeal endoderm
KW - Arch artery development
KW - Tbx1
KW - Pax9
KW - Neural crest
KW - 22q11 deletion syndrome
UR - https://journals.biologists.com/dev/article/146/18/dev177618/224210/Pax9-is-required-for-cardiovascular-development?searchresult=1
U2 - 10.1242/dev.177618
DO - 10.1242/dev.177618
M3 - Article
SN - 0950-1991
VL - 146
JO - Development
JF - Development
IS - 18
M1 - dev177618
ER -