The del22q11.2 Candidate Gene
            <i>Tbx1</i>
            Controls Regional Outflow Tract Identity and Coronary Artery Patterning

Théveniau-Ruissy, Magali; Dandonneau, Mathieu; Mesbah, Karim; Ghez, Olivier; Mattei, Marie-Genevı̀eve; Miquerol, Lucile; Kelly, Robert G.

doi:10.1161/circresaha.108.172189

Cited by 152 publications

(149 citation statements)

References 42 publications

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“…4A; Sema3c-lacZ) showed X-gal staining in the OFT/subpulmonary myocardium and right ventricle, as well as in the neural tube, somites, and limb buds (Fig. 4B-E), consistent with the endogenous expression pattern of Sema3c (9,24,31,32). At E11.5, lacZ expression in the cardiovascular system, including the OFT region, was abolished in four of four independent transgenic embryos harboring the transgene with the Site1 mutation ( Fig.…”

Section: Gata6 Directly Regulates Sema3c and Plxna2 Through A Consenssupporting

confidence: 64%

“…To date, no molecular link has been demonstrated between GATA6 and TBX1. Interestingly, a recent study showed that the expression of Sema3c in the OFT was downregulated in mouse embryos deficient for Tbx1 (31), suggesting that GATA6 may share, at least in part, a common molecular pathway with TBX1 during OFT development (31).…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that SEMA3C and PLXNA2 are directly regulated by GATA6 in humans through consensus binding sites on their enhancer elements and that each of the GATA6 mutations disturbs semaphorin-plexin signaling to varying degrees, resulting in abnormal development of the OFT. During murine cardiovascular development, Sema3c is expressed in the OFT/subpulmonary myocardium and pharyngeal arch arteries (9,24,31), whereas Plxna2 is expressed in the CNC derivatives (10). We established a transgenic mouse system to test in vivo whether Sema3c and Plxna2 expression is directly dependent on GATA transcription factors during OFT development.…”

Section: Gata6 Directly Regulates Sema3c and Plxna2 Through A Consensmentioning

confidence: 99%

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GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling

Kodo

Nishizawa

Furutani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

217

157

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Congenital heart diseases (CHD) occur in nearly 1% of all live births and are the major cause of infant mortality and morbidity. Although an improved understanding of the genetic causes of CHD would provide insight into the underlying pathobiology, the genetic etiology of most CHD remains unknown. Here we show that mutations in the gene encoding the transcription factor GATA6 cause CHD characteristic of a severe form of cardiac outflow tract (OFT) defect, namely persistent truncus arteriosus (PTA). Two different GATA6 mutations were identified by systematic genetic analysis using DNA from patients with PTA. Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. Transgenic analysis further suggests that, in the developing heart, the expression of SEMA3C in the OFT/subpulmonary myocardium and PLXNA2 in the cardiac neural crest contributing to the OFT is dependent on GATA transcription factors. Together, our data implicate mutations in GATA6 as genetic causes of CHD involving OFT development, as a result of the disruption of the direct regulation of semaphorin-plexin signaling.congenital heart disease ͉ persistent truncus arteriosus ͉ cardiac neural crest C ongenital heart diseases (CHD) constitute a major percentage of clinically significant birth defects with an estimated prevalence of 4-10 per 1,000 live infants (1). Cardiac outflow tract (OFT) defects are estimated to account for approximately 30% of CHD (2) and usually require an intervention during the first year of life. A variety of OFT defects results from disturbance of the morphogenetic patterning of the anterior pole of the heart, which is essential for the establishment of separate systemic and pulmonary circulations in higher vertebrates. Persistent truncus arteriosus (PTA), which is attributed to missing septation of the OFT, is recognized as the most severe phenotype of OFT defect, and is often associated with an unfavorable prognosis because complete surgical repair is not always possible (3). Although an improved understanding of possible genetic causes would provide insight into the pathogenesis of CHD and allow for better assessment of disease risk, prenatal diagnosis, and critical information for disease prevention, the etiology of most CHD, including OFT defects, remains unknown because of the multifactorial nature of the diseases (4-6).Based on animal studies, it appears that abnormal development of cardiac neural crest (CNC) cells, an ectoderm-derived cell lineage, contributes significantly to the pathology of OFT defects (7-12). During early embryogenesis, CNC cells arise from the dorsal neural tube and migrate ventrally as mesenchymal cells to populate the OFT, where they coalesce to form the aorticopulmonary septum, which divides the single truncus arteriosus (embryonic OFT) into the aorta and pulmonary artery, resulting in the establishment of separate systemic and pulmonary c...

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Section: Gata6 Directly Regulates Sema3c and Plxna2 Through A Consenssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Gata6 Directly Regulates Sema3c and Plxna2 Through A Consensmentioning

confidence: 99%

See 1 more Smart Citation

GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling

Kodo

Nishizawa

Furutani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

217

157

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“…7 Commonly, the clinical phenotype of individuals with GATA6 mutations involves the OFT, but is distinct from that of DiGeorge/22q11.2 deletion syndrome and, rather, manifests as non-syndromic CHD. To date, no molecular link has been demonstrated between GATA6 and TBX1, 8,9 however, a recent study showed that the expression of Sema3c in the OFT was downregulated in mouse embryos deficient for Tbx1, 10 suggesting that GATA6 may share, at least in part, a common molecular pathway with TBX1 during OFT development.…”

mentioning

confidence: 99%

GATA transcription factors in congenital heart defects: A Commentary on a novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

Kodo

Yamagishi

2010

J Hum Genet

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C ongenital heart defects (CHDs) occur in nearly 1% of all live births and are the major cause of infant mortality and morbidity. In addition, about 3 per every 1000 live births will require some intervention during the first year of life. 1 Despite its clinical importance, the underlying genetic etiology of most CHD remains unknown. Previous studies succeeded in revealing genetic causes of some syndromic or familial CHD, however, there are limited numbers of such cases, and it is still difficult to approach the etiology of the majority of CHD, that manifest non-syndromic and non-familial phenotype, because of their multi-factorial nature.In this issue, Lin et al. report on a novel mutation of a gene encoding a transcription factor, GATA6, as a possible cause of CHD. 2 The authors screened 270 individuals with non-syndromic CHD for the GATA6 gene by direct sequencing, and identified a missense mutation (S184N) in three individuals, one with tetralogy of Fallot and the others with atrial septal defect. Although the incomplete penetrance of the phenotype by this mutation was observed, the mutation was not found in 500 ethnically matched healthy controls. And their subsequent biological analysis revealed the decreased transcriptional activity of GATA6 with the S184N mutation for the gene regulation of several important cardiac factors, suggesting that the GATA6 S184N mutation may have an important role in the pathogenesis of CHD.The first identification of disease-associated mutations of GATA6 in CHD was originally reported by us. 3 We screened mutations of cardiac transcription factors in patients with selected non-syndromic CHD, namely persistent truncus arteriosus, representing the most severe cardiac outflow tract (OFT) defects. Two different GATA6 mutations were identified in two probands, but not in 182 unrelated controls with no CHD. Our subsequent biological analyses revealed that genes encoding the neurovascular guiding molecule semaphorin 3C and its receptor plexin A2 were directly regulated by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. Transgenic analysis further suggested that the expression of semaphorin 3C and plexin A2 in the OFT was dependent on GATA transcription factors during the heart development. Together, our data implicate mutations in GATA6 as novel genetic causes of CHD involving the OFT development, as a result of the disruption of the direct regulation of semaphorin-plexin signaling. Another recent study by Maitra et al. showed two novel sequence variations in GATA6 (A178V and L198V) from the screening of 310 individuals with CHD. 4 These variants were identified in two individuals, one with tetralogy of Fallot and another with atrioventricular septal defect, but not in 288 ethnically matched healthy controls. Biochemical analysis demonstrated that the GATA6 A178V mutant protein resulted in increased transactivation ability for cardiac genes compared with the wildtype. Our first report and subsequent reports by Maitra et al. 4 and Lin et al. 2 in this issue...

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“…Among the last myocardial derivatives of the SHF to be added to the elongating heart tube is future subpulmonary myocardium, a cell population specifically affected in Tbx1 mutant embryos [13]. Asymmetric addition of SHF progenitor cells giving rise to subpulmonary myocardium continues on the left side of the outflow tract up until embryonic day 12.5 in the mouse; furthermore, this late contribution drives rotation of the outflow tract, positioning subpulmonary myocardium on the ventral side of the heart and aligning the ascending aorta with the left ventricle [14].…”

Section: New Insights Into the Role And Regulation Of Noncanonical Wnmentioning

confidence: 99%

Properties of Cardiac Progenitor Cells in the Second Heart Field

Francou

Kelly

2016

Etiology and Morphogenesis of Congenital Heart Disease

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Heart tube elongation occurs by progressive addition of cells from pharyngeal mesoderm to the poles of the heart. These progenitor cells, termed the second heart field, contribute to right ventricular and outflow tract myocardium at the arterial pole of the heart and to atrial myocardium at the venous pole. Perturbation of this process results in congenital heart defects. Since the discovery of this progenitor cell population, much has been learned about the signaling pathways and transcription factors regulating second heart field deployment. However, fundamental questions about the molecular and cellular mechanisms underlying heart tube elongation remain. Here we briefly review a selection of recent findings in the area of second heart field biology and discuss the clinical implications of these new studies for our understanding of the etiology of congenital heart defects.

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The del22q11.2 Candidate Gene Tbx1 Controls Regional Outflow Tract Identity and Coronary Artery Patterning

Cited by 152 publications

References 42 publications

GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling

GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling

GATA transcription factors in congenital heart defects: A Commentary on a novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

Properties of Cardiac Progenitor Cells in the Second Heart Field

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