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

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.

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Conotruncal heart defects and aortic arch anomalies in fetuses with 22q11.2 deletion syndrome

10.21516/2413-1458-2020-19-3-203-209 ◽

2020 ◽

Author(s):

I.V. Novikova, O.M. Khurs, T.V. Demidovich et all

Keyword(s):

Aortic Arch ◽

Heart Defects ◽

22Q11.2 Deletion Syndrome ◽

Ventricular Outflow Tract ◽

Double Outlet Right Ventricle ◽

Interrupted Aortic Arch ◽

Left Ventricular ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Aortic Arch Anomalies

16 second trimester fetuses with 22q11.2 deletion syndrome have been examined at anatomic-pathological investigation. Main cardiovascular diseases were ascending aorta hypoplasia with aortic valve stenosis (n = 6; 37.5%), truncus arteriosus (n = 5; 31.25%), tetralogy of Fallot (n = 3; 18.75%) and double-outlet right ventricle (n = 1; 6.25%). Ventricular septal defect was present in 16 cases. Associated aortic arch anomalies included interrupted aortic arch (n = 9; 56.25%), right aortic arch (n = 6; 37.5%), retroesophageal ring (n = 1; 6.25%) and aberrant right subclavian arteria (n = 5; 31.25%). 5 fetuses had left ventricular outflow tract obstructive lesions with interrupted aortic arch of type B combined with aberrant right subclavian arteria.

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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

10.1101/576660 ◽

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.

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One-Stage Repair of Cardiac and Arch Anomalies without Circulatory Arrest

Asian Cardiovascular and Thoracic Annals ◽

10.1177/021849230301100315 ◽

2003 ◽

Vol 11 (3) ◽

pp. 250-254 ◽

Cited By ~ 1

Author(s):

Kona Samba Murthy ◽

Robert Coelho ◽

Christopher Roy ◽

Snehal Kulkarni ◽

Benjamin Ninan ◽

...

Keyword(s):

Ventricular Septal Defect ◽

Aortic Arch ◽

Septal Defect ◽

Circulatory Arrest ◽

Coarctation Of The Aorta ◽

Innominate Artery ◽

Double Outlet Right Ventricle ◽

Interrupted Aortic Arch ◽

Ischemic Time ◽

Arch Obstruction

Between 1999 and 2002, 23 patients underwent single-stage complete repair of cardiac anomalies and aortic arch obstruction, without circulatory arrest. Median age was 1.2 years. Intracardiac defects included ventricular septal defect in 9, double-outlet right ventricle in 6, d-transposition of the great arteries and ventricular septal defect in 2, subaortic obstruction in 3, and atrial septal defect in 3. Fourteen patients had coarctation of the aorta, 6 had coarctation with hypoplastic aortic arch, and 3 had interrupted aortic arch. Simple techniques were employed such as cannulation of the ascending aorta near the innominate artery and maintaining cerebral and myocardial perfusion. After correction of arch obstruction, intracardiac repair was undertaken. The mean cardiopulmonary bypass time was 169 min, aortic crossclamp time was 51 min, and arch repair took 16 min. There was no operative mortality or neurological deficit. In follow-up of 1–43 months, no patient had residual coarctation. This simplified technique avoids additional procedures, reduces ischemic time, and prevents problems related to circulatory arrest.

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Hospital Outcomes Among Infants With Interrupted Aortic Arch With Simple and Complex Associated Heart Defects

The American Journal of Cardiology ◽

10.1016/j.amjcard.2021.11.032 ◽

2021 ◽

Author(s):

Aura Andrea Sanchez Mejia ◽

Neil Cambronero ◽

Deepa Dongarwar ◽

Hamisu Mohammed Salihu ◽

Maria Anita Vigil-Mallette ◽

...

Keyword(s):

Aortic Arch ◽

Heart Defects ◽

Interrupted Aortic Arch ◽

Hospital Outcomes

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Echocardiographic assessment of interrupted aortic arch

Cardiology in the Young ◽

10.1017/s104795110000559x ◽

1999 ◽

Vol 9 (6) ◽

pp. 562-571 ◽

Cited By ~ 15

Author(s):

Renate Kaulitz ◽

Richard A. Jonas ◽

Mary E. van der Velde

Keyword(s):

Ventricular Septal Defect ◽

Aortic Arch ◽

Surgical Procedure ◽

Septal Defect ◽

Heart Defects ◽

Interrupted Aortic Arch ◽

Additional Information ◽

Intracardiac Repair ◽

Direct Anastomosis ◽

Operative Notes

AbstractBackgroundIn patients with interrupted aortic arch echocardiography provides detailed information about the anatomy of the aortic arch and the associated cardiac anomalies. Only a few reports have evaluated the reliability of this non-invasive diagnostic procedure by correlation with angiographic and surgical findings.MethodsFrom 1988 through 1993, 45 infants with interrupted arch underwent surgical repair (mean age 13.02 days). Of the patients, 33 had interruption of the arch between the left common carotid and subclavian arteries; 25 patients had a ventricular septal defect, and the remaining 20 had coexisting complex congenital heart defects. Preoperative diagnosis was made exclusively by echocardiography in 25 of the patients. Accuracy of echocardiographic diagnosis was evaluated retrospectively by comparing preoperative studies with angiography and surgical reports. We then investigated whether the morphologic features of the interrupted arch might influence surgical procedure or outcome.ResultsIntracardiac anatomy was accurately diagnosed by echocardiography in all cases; in 2 patients angiography provided additional information concerning the morphology of the aortic arch. Operative notes described differences in morphology of the arch in 7 patients, but these did not influence the surgical procedure. Direct anastomosis of the interrupted segments was possible in 38 patients, and 36 patients underwent primary intracardiac repair. Echocardiographic measurements revealed that the diameter of the ascending aorta was related to the number of vessels originating from the proximal aortic arch. The distance between the interrupted segments was significantly different according to the site of interruption, but not between cases with an isolated ventricular septal defect versus those with complex heart disease. It did not influence the method of arch repair, nor was it related to recurrent or residual obstruction.ConclusionPreoperative echocardiography offers accurate and complete diagnosis in the critically ill neonate with interrupted aortic arch and associated intracardiac abnormalities.

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Neonatal Death Caused by Interrupted Aortic Arch Associated With 22q11.2 Deletion Syndrome

American Journal of Forensic Medicine & Pathology ◽

10.1097/paf.0000000000000454 ◽

2019 ◽

Vol 40 (2) ◽

pp. 178-182

Author(s):

Norihiro Shinkawa ◽

Masatoshi Yamaguchi ◽

Mamoru Ozaki ◽

Nobuhiro Yukawa

Keyword(s):

Aortic Arch ◽

Neonatal Death ◽

22Q11.2 Deletion Syndrome ◽

Interrupted Aortic Arch ◽

Deletion Syndrome ◽

22Q11.2 Deletion

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

Circulation ◽

10.1161/circ.116.suppl_16.ii_185-b ◽

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.

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An Unusual Association: Total Anomalous Pulmonary Venous Return and Aortic Arch Obstruction in Patients with Cat Eye Syndrome

Journal of Pediatric Genetics ◽

10.1055/s-0039-1701020 ◽

2020 ◽

Author(s):

Jason L. Williams ◽

Marie T. McDonald ◽

Bryce A. Seifert ◽

Kristen L. Deak ◽

Catherine W. Rehder ◽

...

Keyword(s):

Aortic Arch ◽

Venous Return ◽

Heart Defects ◽

Genetic Defect ◽

Coarctation Of The Aorta ◽

Interrupted Aortic Arch ◽

Aberrant Right Subclavian Artery ◽

Cat Eye Syndrome ◽

Arch Obstruction ◽

Anomalous Pulmonary Venous Return

AbstractCat eye syndrome (CES) is a rare genetic defect, characterized by iris colobomas, preauricular skin tags, and anal malformations. Affecting 1 in 150,000 people, this defect is caused by duplication or triplication of the proximal long (q) arm of chromosome 22. Congenital heart disease is associated with CES. One of the most common heart defects in patients with CES is total anomalous pulmonary venous return (TAPVR). We report patients with a rare association of concomitant TAPVR and aortic arch obstruction: one with interrupted aortic arch and the other with coarctation of the aorta with an aberrant right subclavian artery.

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