An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation

Nadeau, Mathieu; Georges, Romain O.; Laforest, Brigitte; Yamak, Abir; Lefèbvre, Chantal; Beauregard, Janie; Paradis, Pierre; Bruneau, Benoit G.; Andelfinger, Grégor; Nemer, Mona

doi:10.1073/pnas.0914888107

Cited by 65 publications

(47 citation statements)

References 56 publications

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“…S6). The expression of other genes crucial for endocardial cushion and valve development, including Bmp4 (Jiao et al, 2003), Notch1 (Timmerman et al, 2004), Gata4 (Rivera-Feliciano et al, 2006), Tbx5 (Nadeau et al, 2010) and Nfatc1 (de la Pompa et al, 1998;Ranger et al, 1998) was unchanged in Tbx20 CKO hearts (supplementary material Figs S7, S8). These results suggest that endocardial Tbx20 is not essential for EMT initiation in the AVC or OFT.…”

Section: Research Article Development 140 (15)mentioning

confidence: 99%

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Cai

Zhang

et al. 2013

Development

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SUMMARYCardiac valves are essential to direct forward blood flow through the cardiac chambers efficiently. Congenital valvular defects are prevalent among newborns and can cause an immediate threat to survival as well as long-term morbidity. Valve leaflet formation is a rigorously programmed process consisting of endocardial epithelial-mesenchymal transformation (EMT), mesenchymal cell proliferation, valve elongation and remodeling. Currently, little is known about the coordination of the diverse signals that regulate endocardial cushion development and valve elongation. Here, we report that the T-box transcription factor Tbx20 is expressed in the developing endocardial cushions and valves throughout heart development. Ablation of Tbx20 in endocardial cells causes severe valve elongation defects and impaired cardiac function in mice. Our study reveals that endocardial Tbx20 is crucial for valve endocardial cell proliferation and extracellular matrix development, but is not required for initiation of EMT. Elimination of Tbx20 also causes aberrant Wnt/β-catenin signaling in the endocardial cushions. In addition, Tbx20 regulates Lef1, a key transcriptional mediator for Wnt/β-catenin signaling, in this developmental process. Our study suggests a model in which Tbx20 regulates the Wnt pathway to direct endocardial cushion maturation and valve elongation, and provides new insights into the etiology of valve defects in humans.

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Section: Research Article Development 140 (15)mentioning

confidence: 99%

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Cai

Zhang

et al. 2013

Development

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“…Total RNA was isolated from hearts of E12.5 embryos or from LV and IVS at postnatal day 30 with TRIzol reagent (Invitrogen); cDNAs were generated using the Omniscript RT kit (Qiagen), and Q-PCR was performed as previously described (67). See Supplemental Table 1 for primer sequences.…”

Section: Methodsmentioning

confidence: 99%

Loss of Gata5 in mice leads to bicuspid aortic valve

Laforest¹,

Andelfinger²,

Nemer³

2011

J. Clin. Invest.

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163

146

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Bicuspid aortic valve (BAV), the leading congenital heart disease, occurs in 1%-2% of the population. Genetic studies suggest that BAV is an autosomal-dominant disease with reduced penetrance. However, only 1 gene, NOTCH1, has been linked to cases of BAV. Here, we show that targeted deletion of Gata5 in mice leads to hypoplastic hearts and partially penetrant BAV formation. Endocardial cell-specific inactivation of Gata5 led to BAV, similar to that observed in Gata5 -/-mice. In all cases, the observed BAVs resulted from fusion of the right-coronary and noncoronary leaflets, the subtype associated with the more severe valve dysfunction in humans. Neither endocardial cell proliferation nor cushion formation was altered in the absence of Gata5. Rather, defective endocardial cell differentiation, resulting from the deregulation of several components of the Notch pathway and other important endocardial cell regulators, may be the underlying mechanism of disease. The results unravel a critical cell-autonomous role for endocardial Gata5 in aortic valve formation and identify GATA5 as a potential gene responsible for congenital heart disease in humans. Mice with mutated Gata5 alleles represent unique models to dissect the mechanisms underlying degenerative aortic valve disease and to develop much-needed preventive and therapeutic interventions.

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“…TBX5 mutations are associated with HoltOram syndrome, which is characterized by upper limb and cardiac malformations (ASD, VSD) (Basson et al, 1997;Li et al, 1997). These limb and cardiac defects are seen in mice with a heterozygous Tbx5 mutation (Bruneau et al, 2001), and loss of endocardial Tbx5 causes excessive apoptosis in primary atrial septum, possibly through disruption of the Tbx5/Gata4-Nos3 pathway (Nadeau et al, 2010). (Lee et al, 1997;Jiang et al, 2002;Li et al, 2010) Rxra Global PTA, DORV, VSD, AVSD Variable AV cushion defects (Gruber et al, 1996) For definitions, see Glossary, Box 1.…”

Section: T-box Genesmentioning

confidence: 99%

Partitioning the heart: mechanisms of cardiac septation and valve development

et al. 2012

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Heart malformations are common congenital defects in humans. Many congenital heart defects involve anomalies in cardiac septation or valve development, and understanding the developmental mechanisms that underlie the formation of cardiac septal and valvular tissues thus has important implications for the diagnosis, prevention and treatment of congenital heart disease. The development of heart septa and valves involves multiple types of progenitor cells that arise either within or outside the heart. Here, we review the morphogenetic events and genetic networks that regulate spatiotemporal interactions between the cells that give rise to septal and valvular tissues and hence partition the heart.

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An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation

Cited by 65 publications

References 56 publications

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Loss of Gata5 in mice leads to bicuspid aortic valve

Partitioning the heart: mechanisms of cardiac septation and valve development

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