β-Catenin directly regulates
            <i>Islet1</i>
            expression in cardiovascular progenitors and is required for multiple aspects of cardiogenesis

Lin, Lizhu; Cui, Li; Zhou, Wenlai; Dufort, Daniel; Zhang, Xiaoxue; Cai, Chen-Leng; Bu, Lei; Yang, Lei; Martin, Jody; Kemler, Rolf; Rosenfeld, Michael G.; Chen, Ju; Evans, Sylvia M.

doi:10.1073/pnas.0700923104

Cited by 241 publications

(220 citation statements)

References 45 publications

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“…In contrast, SHF specification was severely disturbed, resulting in a lack of cardiac looping and proper outflow tract and right ventricle formation. It was recently shown that defects in right ventricle and outflow tract formation are also observed when competence to Wnt signaling was removed during and after SHF specification (48,49). Our results using both loss-and gain-of-function mutations of ␤-catenin suggest that it may be the amount of Wnt/␤-catenin signaling that is important for early cardiogenesis.…”

Section: Discussionmentioning

confidence: 48%

Distinct roles of Wnt/β-catenin and Bmp signaling during early cardiogenesis

Klaus

Saga

Taketo

et al. 2007

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

256

208

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Heart formation requires the coordinated recruitment of multiple cardiac progenitor cell populations derived from both the first and second heart fields. In this study, we have ablated the Bmp receptor 1a and the Wnt effector ␤-catenin in the developing heart of mice by using MesP1-cre, which acts in early mesoderm progenitors that contribute to both first and second heart fields. Remarkably, the entire cardiac crescent and later the primitive ventricle were absent in MesP1-cre; BmpR1a lox/lox mutants. Although myocardial progenitor markers such as Nkx2-5 and Isl1 and the differentiation marker MLC2a were detected in the small, remaining cardiac field in these mutants, the first heart field markers, eHand and Tbx-5, were not expressed. We conclude from these results that Bmp receptor signaling is crucial for the specification of the first heart field. In MesP1-cre; ␤-catenin lox/lox mutants, cardiac crescent formation, as well as first heart field markers, were not affected, although cardiac looping and right ventricle formation were blocked. Expression of Isl1 and Bmp4 in second heart field progenitors was strongly reduced. In contrast, in a gain-of-function mutation of ␤-catenin using MesP1-cre, we revealed an expansion of Isl1 and Bmp4 expressing cells, although the heart tube was not formed. We conclude from these results that Wnt/␤-catenin signaling regulates second heart-field development, and that a precise amount and/or timing of Wnt/␤-catenin signaling is required for proper heart tube formation and cardiac looping.BmpR1a ͉ first heart field ͉ heart looping ͉ mesoderm patterning ͉ second heart field

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Section: Discussionmentioning

confidence: 48%

Distinct roles of Wnt/β-catenin and Bmp signaling during early cardiogenesis

Klaus

Saga

Taketo

et al. 2007

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

256

208

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“…The tissue-specific downregulation of ␤-catenin in the SHF using different Cre mouse lines leads to a reduction of Isl1-positive cells in comparison to wild-type mice as well as a loss of the SHF-derived OFT and right ventricle. 79 -83 Moreover, it has been shown by chromatin immunoprecipitation experiments that ␤-catenin is directly binding and positively regulating the Isl1 promotor 83 whereas others reported a negative regulation. 47 Also, FGF ligands were supposed to be downstream of ␤-catenin signaling.…”

Section: Cardiac Specification: Positive Influence Of Noncanonical Wnmentioning

confidence: 99%

The Multiple Phases and Faces of Wnt Signaling During Cardiac Differentiation and Development

Gessert

Kühl

2010

Circulation Research

358

310

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Understanding heart development on a molecular level is a prerequisite for uncovering the causes of congenital heart diseases. Therapeutic approaches that try to enhance cardiac regeneration or that involve the differentiation of resident cardiac progenitor cells or patient-specific induced pluripotent stem cells will also benefit tremendously from this knowledge. Wnt proteins have been shown to play multiple roles during cardiac differentiation and development. They are extracellular growth factors that activate different intracellular signaling branches. Here, we summarize our current understanding of how these factors affect different aspects of cardiogenesis, starting from early specification of cardiac progenitors and continuing on to later developmental steps, such as morphogenetic processes, valve formation, and establishment of the conduction system. (Circ Res. 2010;107:186-199.)

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“…Missense mutation of low-density lipoprotein receptor-related protein 6 in humans, which encodes a coreceptor of Wnt results in early coronary artery disease and multiple cardiovascular risk factors (51). In addition, a TCF/ Lef-LacZ reporter of ␤-catenin transcriptional activity has identified both the proepicardium and the epicardium as active targets of Wnt-mediated transcriptional activity (27). Here, we have demonstrated progenitor differentiation into the smooth muscle lineage is largely impaired in the epiBC-KO epicardium.…”

Section: Impaired Development Of Epdcs and Myocardial Growth Defectsmentioning

confidence: 99%

mentioning

confidence: 99%

“…19). In the heart, Wnt signaling plays a pivotal role in cardiomyocyte specification, and both activation and inhibition of Wnt signaling affect the formation of the cardiomyocyte compartment (20-27), suggesting that the muscular component of the heart depends on the cellular context in which Wnt stimulation occurs (27).To explore the role of Wnt/␤-catenin in the development of coronary progenitor cells and its implication on cardiac morphogenesis, we have generated a conditional ␤-catenin mutant mouse lacking ␤-catenin expression in the proepicardium and its derivatives. …”

mentioning

confidence: 99%

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Epicardium-derived progenitor cells require β-catenin for coronary artery formation

Zamora

Männer²,

Ruiz‐Lozano³

2007

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

158

136

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We have previously identified several members of the Wnt/␤-catenin pathway that are differentially expressed in a mouse model with deficient coronary vessel formation. Systemic ablation of ␤-catenin expression affects mouse development at gastrulation with failure of both mesoderm development and axis formation. To circumvent this early embryonic lethality and study the specific role of ␤-catenin in coronary arteriogenesis, we have generated conditional ␤-catenin-deletion mutant animals in the proepicardium by interbreeding with a Cre-expressing mouse that targets coronary progenitor cells in the proepicardium and its derivatives. Ablation of ␤-catenin in the proepicardium results in lethality between embryonic day 15 and birth. Mutant mice display impaired coronary artery formation, whereas the venous system and microvasculature are normal. Analysis of proepicardial ␤-catenin mutant cells in the context of an epicardial tracer mouse reveals that the formation of the proepicardium, the migration of proepicardial cells to the heart, and the formation of the primitive epicardium are unaffected. However, subsequent processes of epicardial development are dramatically impaired in epicardial-␤-catenin mutant mice, including failed expansion of the subepicardial space, blunted invasion of the myocardium, and impaired differentiation of epicardium-derived mesenchymal cells into coronary smooth muscle cells. Our data demonstrate a functional role of the epicardial ␤-catenin pathway in coronary arteriogenesis. The embryonic epicardium originates from a primarily extracardiac primordium, the proepicardum, which is located at the septum transversum near the venous pole of the heart (2, 3). In mouse embryos, proepicardial cells reach the heart predominantly in the form of free-floating vesicles that traverse the pericardial cavity, adhere to the initially naked myocardial surface, and subsequently form the epicardial covering of the heart (reviewed in ref. 1). The recruitment of coronary vessel progenitor cells from the proepicardium and embryonic epicardium involves several steps of epithelial-mesenchymal transition (EMT). As a result of proepicardial EMT, the extracellular matrix of free-floating proepicardial vesicles becomes populated with mesenchymal cells (4-8). Subsequently, the primitive epicardium gives rise to the subepicardial mesenchyme, also by means of EMT.Recent data suggest that the primitive epicardium and epicardium-derived cells (EPDCs) modulate the maturation of other cardiac components, including the embryonic myocardium and the cardiac conduction system (9-14). We have previously shown that the embryonic epicardium is a key signaling tissue responsible for the transmission of the morphogenic signal derived from retinoic acid and identified several components of the Wnt/␤-catenin signaling pathway that are down-regulated upon retinoid signaling deficiency, in particular, ␤-catenin and its activator Wnt9b (15).However, it remains to be shown whether Wnt/␤-catenin signaling plays a specific role in the de...

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β-Catenin directly regulates Islet1 expression in cardiovascular progenitors and is required for multiple aspects of cardiogenesis

Cited by 241 publications

References 45 publications

Distinct roles of Wnt/β-catenin and Bmp signaling during early cardiogenesis

Distinct roles of Wnt/β-catenin and Bmp signaling during early cardiogenesis

The Multiple Phases and Faces of Wnt Signaling During Cardiac Differentiation and Development

Epicardium-derived progenitor cells require β-catenin for coronary artery formation

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