Abstract
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.
Original language | English |
---|---|
Article number | dev177618 |
Number of pages | 16 |
Journal | Development |
Volume | 146 |
Issue number | 18 |
Early online date | 23 Sept 2019 |
DOIs | |
Publication status | Published - Sept 2019 |
Bibliographical note
We thank Jessica Addison, Kathleen Allinson and Divya Venkatesh for technicalassistance, Sushma Grellscheid for facilitating the RNA-seq experiment, and
Nicoletta Bobola for critically reading the manuscript. Tbx1 +/– mice were obtained
from Robert Kelly and Virginia Papaioannou. We acknowledge the Newcastle
University Flow Cytometry Core Facility (FCCF) for assistance with the generation of
flow cytometry data.
Data Availability Statement
The RNA-seq data have been deposited in GEO under accession numberGSE128087.
Keywords
- Pharyngeal endoderm
- Arch artery development
- Tbx1
- Pax9
- Neural crest
- 22q11 deletion syndrome