GATA5 interacts with GATA4 and GATA6 in outflow tract development

Laforest, Brigitte; Nemer, Mona

doi:10.1016/j.ydbio.2011.07.037

Cited by 88 publications

(96 citation statements)

References 63 publications

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“…In zebrafish, targeted disruption of the GATA5 gene resulted in embryonic lethality due to defects in endocardial and myocardial differentiation and migration, a similar phenotype to cardia bifida of GATA4-null zebrafish (73). Although the GATA5-null mice were viable and had no apparent cardiac defects, the mice that were compound heterozygous for GATA5 and GATA4 or for GATA5 and GATA6 knockout died embryonically or perinatally because of severe defects of the outflow tract development, including double outlet right ventricle and ventricular septal defect (74). These experimental findings highlight the exquisite sensitivity of the developing cardiovascular system to the levels of GATA4, GATA5 and GATA6, and indicate that these GATA factors act synergistically to regulate target genes.…”

Section: Discussionmentioning

confidence: 98%

Somatic GATA5 mutations in sporadic tetralogy of Fallot

Huang

Xue

et al. 2014

International Journal of Molecular Medicine

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Abstract. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, with high morbidity and mortality rates. Accumulating evidence has demonstrated that genetic defects play an important role in the pathogenesis of TOF. However, the molecular basis of TOF in the majority of patients remains to be determined. In the present study, sequence analysis of the coding exons and exon-intron boundaries of GATA5, a gene encoding a zinc finger-containing transcriptional factor crucial for cardiogenesis, was performed on genomic DNA isolated from resected cardiac tissue and matched blood samples of 85 unrelated patients who underwent surgical repair of TOF. Genotyping was performed on the cardiac tissue and matched blood samples from 63 unrelated patients who underwent cardiac valve replacement due to rheumatic heart disease as well as the blood samples obtained from 200 unrelated healthy individuals. The functional effect of the mutations was evaluated by using a luciferase reporter assay system. As a result, the novel heterozygous GATA5 mutations, p.D203E and p.Y208X, were found in the cardiac tissues of two TOF patients, respectively. There were no mutations in the cardiac tissues obtained from 63 patients with rheumatic heart disease nor in the blood samples obtained from the 348 subjects. Functional analysis revealed that the GATA5 mutants were consistently associated with significantly decreased transcriptional activity compared with their wild-type counterpart. Thus, results of this study showed an association of somatic GATA5 mutations with TOF, providing further insight into the underlying molecular mechanism of TOF.

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Section: Discussionmentioning

confidence: 98%

Somatic GATA5 mutations in sporadic tetralogy of Fallot

Huang

Xue

et al. 2014

International Journal of Molecular Medicine

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“…Our results indicate that Notch1 is required within the endothelial cell lineage for proper OFT development and semilunar valve remodeling; however, the cell lineages with which Notch1 communicates have not been well defined. Similar to Notch1, deletion of Gata5 or Alk2 in the OFT endothelial (endocardial) and endothelial‐derived mesenchymal cells is sufficient to cause BAV 27, 28, 29. In addition, the cardiac neural crest is critical for the development of the cardiac OFT because loss of BMP signaling via the receptor ALK2 has been shown to cause persistent truncus arteriosus, improper cardiac neural crest migration causes OFT defects, and the loss of Rho kinase signaling within neural crest cells gives rise to BAV 30, 31, 32.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Koenig

Bosse

Majumdar

et al. 2016

JAHA

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BackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal‐dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1‐haploinsufficient adult mice backcrossed into a Nos3‐null background.Methods and ResultsHere, we described the congenital cardiac abnormalities in Notch1 +/− ;Nos3 −/− embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1 +/− ;Nos3 −/− embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1 +/− ;Nos3 −/− embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial‐derived cells in a Nos3‐null background and found that Notch1 fl/+;Tie2‐Cre +/− ;Nos3 −/− mice recapitulate the congenital cardiac phenotype of Notch1 +/− ;Nos3 −/− embryos.ConclusionsOur data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.

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“…Although the mice heterozygous for either GATA4 or GATA6 deletion are viable without overt cardiovascular defects, the mice that are compound heterozygous for both GATA4 and GATA6 targeted disruptions die by E13.5 with 100% penetrance, exhibiting a phenotypic spectrum of cardiovascular defects, including ventricular septal defect, persistent truncus arteriosus, myocardial hypoplasia, reduced myocardial proliferation, and impaired differentiation of vascular smooth muscle cells (53)(54)(55). Similarly, compound null of a GATA5 and a GATA6 allele also gives rise to double outlet right ventricle and ventricular septal defect in mice (56). These results from experimental animals demonstrate an exquisite sensitivity of the developing cardiovascular system to the levels of GATA4, GATA5 and GATA6, and indicate that these GATA factors act synergistically to regulate downstream target genes.…”

Section: Discussionmentioning

confidence: 99%

Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot

Huang

Xue

et al. 2012

International Journal of Molecular Medicine

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Abstract. Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease associated with significant morbidity and mortality in humans. However, the molecular etiology underlying TOF in most patients remains largely unknown. In the present study, sequence analysis of the GATA6 gene was performed from fresh-frozen cardiac tissues and matched blood samples of 52 unrelated patients who underwent surgical repair of TOF. The cardiac tissues and matched blood specimens from 46 patients who underwent cardiac valve replacement due to rheumatic heart disease and blood samples from 200 healthy individuals as controls were genotyped. The functional characteristics of the mutations were assessed using a luciferase reporter assay system. Based on the results, two novel heterozygous GATA6 mutations, p.G367X and p.G394C, were identified in the cardiac tissues of 2 TOF patients, respectively. No mutations were found in the cardiac tissues from 46 patients with rheumatic heart disease and in the blood samples from the 298 participants. Functional analysis demonstrated that the GATA6 mutants were consistently associated with significantly reduced transcriptional activation compared with their wildtype counterpart. This is the first report on the link of somatic GATA6 mutation to TOF, providing novel insight into the molecular mechanism involved in TOF.

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GATA5 interacts with GATA4 and GATA6 in outflow tract development

Cited by 88 publications

References 63 publications

Somatic GATA5 mutations in sporadic tetralogy of Fallot

Somatic GATA5 mutations in sporadic tetralogy of Fallot

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot

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