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

2019 ◽  
Author(s):  
Helen M. Phillips ◽  
Catherine A. Stothard ◽  
Wasay Mohiuddin Shaikh Qureshi ◽  
Anastasia I. Kousa ◽  
J. Alberto Briones-Leon ◽  
...  
Keyword(s):  
Aortic Arch ◽  
Genetic Interaction ◽  
Interrupted Aortic Arch ◽  
Outflow Tract ◽  
Pharyngeal Arch ◽  
Cardiovascular Development ◽  
Developmental Defects ◽  
Pharyngeal Endoderm ◽  
Pharyngeal Arch Artery ◽  
Aortic Arch Arteries

AbstractDevelopmental 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 statementPax9 is required for outflow tract and aortic arch development, and functions together with Tbx1 in the pharyngeal endoderm for 4th arch artery formation.

scholarly journals Pax9 and Gbx2 Interact in the Pharyngeal Endoderm to Control Cardiovascular Development

2020 ◽  
Vol 7 (2) ◽  
pp. 20
Author(s):  
Catherine A. Stothard ◽  
Silvia Mazzotta ◽  
Arjun Vyas ◽  
Jurgen E. Schneider ◽  
Timothy J. Mohun ◽  
...  
Keyword(s):  
Aortic Arch ◽  
Regulatory Networks ◽  
Genetic Interaction ◽  
Heart Defects ◽  
Double Outlet Right Ventricle ◽  
Interrupted Aortic Arch ◽  
Deletion Syndrome ◽  
Cardiovascular Development ◽  
Pharyngeal Endoderm ◽  
Regulated Gene Expression

The correct formation of the aortic arch arteries depends on a coordinated and regulated gene expression profile within the tissues of the pharyngeal arches. Perturbation of the gene regulatory networks in these tissues results in congenital heart defects affecting the arch arteries and the outflow tract of the heart. Aberrant development of these structures leads to interruption of the aortic arch and double outlet right ventricle, abnormalities that are a leading cause of morbidity in 22q11 Deletion Syndrome (DS) patients. We have recently shown that Pax9 functionally interacts with the 22q11DS gene Tbx1 in the pharyngeal endoderm for 4th pharyngeal arch artery morphogenesis, with double heterozygous mice dying at birth with interrupted aortic arch. Mice lacking Pax9 die perinatally with complex cardiovascular defects and in this study we sought to validate further potential genetic interacting partners of Pax9, focussing on Gbx2 which is down-regulated in the pharyngeal endoderm of Pax9-null embryos. Here, we describe the Gbx2-null cardiovascular phenotype and demonstrate a genetic interaction between Gbx2 and Pax9 in the pharyngeal endoderm during cardiovascular development.

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

Development ◽  
2019 ◽  
Vol 146 (18) ◽  
pp. dev177618 ◽  
Author(s):  
Helen M. Phillips ◽  
Catherine A. Stothard ◽  
Wasay M. Shaikh Qureshi ◽  
Anastasia I. Kousa ◽  
J. Alberto Briones-Leon ◽  
...  
Keyword(s):  
Pharyngeal Arch ◽  
Cardiovascular Development ◽  
Pharyngeal Endoderm ◽  
Pharyngeal Arch Artery

A genetic link between Tbx1 and fibroblast growth factor signaling

Development ◽  
2002 ◽  
Vol 129 (19) ◽  
pp. 4605-4611 ◽  
Author(s):  
Francesca Vitelli ◽  
Ilaria Taddei ◽  
Masae Morishima ◽  
Erik N. Meyers ◽  
Elizabeth A. Lindsay ◽  
...  
Keyword(s):  
Aortic Arch ◽  
Expression Patterns ◽  
Pharyngeal Arch ◽  
Growth Factor Signaling ◽  
Expression Domain ◽  
Primary Defect ◽  
Genetic Link ◽  
Pharyngeal Endoderm ◽  
Pharyngeal Arch Arteries ◽  
Tbx1 Haploinsufficiency

Tbx1 haploinsufficiency causes aortic arch abnormalities in mice because of early growth and remodeling defects of the fourth pharyngeal arch arteries. The function of Tbx1 in the development of these arteries is probably cell non-autonomous, as the gene is not expressed in structural components of the artery but in the surrounding pharyngeal endoderm. We hypothesized that Tbx1 may trigger signals from the pharyngeal endoderm directed to the underlying mesenchyme. We show that the expression patterns of Fgf8 and Fgf10, which partially overlap with Tbx1 expression pattern, are altered in Tbx1–/– mutants. In particular, Fgf8 expression is abolished in the pharyngeal endoderm. To understand the significance of this finding for the pathogenesis of the mutant Tbx1 phenotype, we crossed Tbx1 and Fgf8 mutants. Double heterozygous Tbx1+/–;Fgf8+/– mutants present with a significantly higher penetrance of aortic arch artery defects than do Tbx1+/–;Fgf8+/+ mutants, while Tbx1+/+;Fgf8+/– animals are normal. We found that Fgf8 mutation increases the severity of the primary defect caused by Tbx1 haploinsufficiency, i.e. early hypoplasia of the fourth pharyngeal arch arteries, consistent with the time and location of the shared expression domain of the two genes. Hence, Tbx1 and Fgf8 interact genetically in the development of the aortic arch. Our data provide the first evidence of a genetic link between Tbx1 and FGF signaling, and the first example of a modifier of the Tbx1 haploinsufficiency phenotype. We speculate that the FGF8 locus might affect the penetrance of cardiovascular defects in individuals with chromosome 22q11 deletions involving TBX1.

Abstract 939: Galpha-i Signaling in Neural Crest Cells is Required for Normal Migration of Cardiac Neural Crest Cells, Cardiac Development, and Survival

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kathleen M Ruppel ◽  
Hiroshi Kataoka ◽  
Michelle Iwaki ◽  
Ivo Cornelissen ◽  
Shaun R Coughlin
Keyword(s):  
Neural Crest ◽  
Signaling Pathways ◽  
Aortic Arch ◽  
G Protein ◽  
Heart Defects ◽  
Neural Crest Cells ◽  
Outflow Tract ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Cardiovascular Development

G protein coupled receptors (GPCRs) have long been known to play crucial roles in transducing environmental signals to the adult cardiovascular system. In recent years, the roles of G protein-mediated signaling pathways in orchestrating the interactions of different tissues during cardiovascular development have become increasingly evident. To analyze the role of G protein signaling pathways in vivo we have generated mice where the function of the heterotrimeric G alpha subunit Gai can be ablated in a cell type specific manner utilizing the Cre-loxP system. We have mated these mice to two different neural crest-specific Cre lines in order to probe the effects of loss of Gai mediated signaling on the ability of neural crest cells (NCC) to contribute to the developing outflow tract and aortic arch arteries. METHODS: We have generated mice that express the Gai-inhibiting pertussis toxin S1 subunit (PTX) from the ROSA26 locus in a Cre recombination dependent manner (ROSA-PTX mice). These were mated to mice expressing either the Wnt1 Cre or P0 Cre transgene. Wnt1Cre is active in both premigratory and migratory NCC, whereas P0Cre is active only in migratory NCC and their derivatives. RESULTS: P0Cre-ROSA-PTX mice were normal at birth and demonstrated no structural heart defects. In contrast, Wnt1Cre-ROSA-PTX mice were present in normal numbers at late gestation but died perinatally due in part to cardiac outflow tract defects. Excision reporter and in situ hybridization studies suggest this is secondary to a delay/blockage of cardiac NCC migration into the developing outflow tract. NCC migration into the pharyngeal arches was unaffected in these mice and no craniofacial, thymic, or aortic arch abnormalities were observed. CONCLUSIONS: These results indicate that Gai-mediated signaling is required in premigratory or early migratory cardiac NCC for normal development of the outflow tract. In contrast, endothelin A receptor knockout mice (currently the only GPCR knock out with a neural crest phenotype) are thought to exhibit defects of postmigratory NCC function. RNA profiling of NCC for GPCRs involved in this Gai-dependent pathway has revealed several potential candidate receptors, including orphan receptors. Further analysis of these receptors is underway.

Management of Interrupted Aortic Arch With Associated Anomalies: A Single-Center Experience

2021 ◽  
Vol 12 (6) ◽  
pp. 706-714
Author(s):  
Mehmet A. Onalan ◽  
Bahar Temur ◽  
Selim Aydın ◽  
Dilek Suzan ◽  
Ibrahim H. Demir ◽  
...  
Keyword(s):  
Aortic Arch ◽  
Left Ventricular Outflow Tract ◽  
Ventricular Outflow Tract ◽  
Interrupted Aortic Arch ◽  
Left Ventricular ◽  
Outflow Tract ◽  
Associated Anomalies ◽  
Ventricular Outflow Tract Obstruction ◽  
Left Ventricular Outflow ◽  
Aortic Arch Repair

Objectives Interrupted aortic arch (IAA) includes a broad spectrum of associated anomalies. In this study, we present our surgical management and patient-specific decisions regarding IAA anomalies with early- and mid-term outcomes. Methods The medical records of 25 patients undergoing IAA repair between 2014 and 2019 were retrospectively reviewed. Sixteen patients had type B (64%) interruptions, 7 had type A (28%) interruptions, and 2 had type C (8%) interruptions. Fourteen patients had an isolated ventricular septal defect, and 3 of them had associated left ventricular outflow tract obstruction. Other associated anomalies were functional single ventricle (n = 5), Taussig–Bing anomaly (n = 3), aortopulmonary window (n = 1), multiple ventricular septal defects (n = 1), and truncus arteriosus with dextrocardia (n = 1). The initial operation age was 17.2 ± 14 (range: 1 - 60) days. Results Single-stage total repair was performed for 15 patients. Six patients underwent aortic arch repair and pulmonary artery banding. Four patients with left ventricular outflow tract obstruction or who were premature underwent the hybrid procedure. The aortic arch repair was performed in 16 cases (64%) by the anterior patch augmentation technique, in 3 cases (12%) by the reverse left subclavian artery flap technique, and in 3 cases (12%) by direct end-to-end anastomosis. Postoperative early mortality occurred in 4 (16%) patients, and sternal closure was delayed in 13 (52%) patients. Three patients who underwent a hybrid procedure due to left ventricular outflow tract obstruction underwent biventricular repair 8 to 13 months later. Eight patients (38%) required reintervention due to arch restenosis during the follow-up period. The mean follow-up was 37.1 ± 21.7 months. Conclusion Planning surgical treatment according to the characteristics of the patients and accompanying anomalies may improve the results.

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