Epicardium is required for the full rate of myocyte proliferation and levels of expression of myocyte mitogenic factors FGF2 and its receptor, FGFR‐1, but not for transmural myocardial patterning in the embryonic chick heart

Pennisi, David J.; Ballard, Victoria L. T.; Matsukawa, Takashi

doi:10.1002/dvdy.10360

Cited by 98 publications

(122 citation statements)

References 70 publications

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“…48,68,113,114 In mice, Fgf-9, Fgf-16, and Fgf-20 are expressed in epicardium in partially overlapping patterns starting at E10. 68 Fgf-9 mutant mice die at birth and show a hypoplastic left ventricle associated with weak CM proliferation.…”

Section: Fibroblast Growth Factormentioning

confidence: 99%

Signaling During Epicardium and Coronary Vessel Development

Pérez‐Pomares

Pompa

2011

Circulation Research

128

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Abstract:The epicardium, the tissue layer covering the cardiac muscle (myocardium), develops from the proepicardium, a mass of coelomic progenitors located at the venous pole of the embryonic heart. Proepicardium cells attach to and spread over the myocardium to form the primitive epicardial epithelium. The epicardium subsequently undergoes an epithelial-to-mesenchymal transition to give rise to a population of epicardiumderived cells, which in turn invade the heart and progressively differentiate into various cell types, including cells of coronary blood vessels and cardiac interstitial cells. Epicardial cells and epicardium-derived cells signal to the adjacent cardiac muscle in a paracrine fashion, promoting its proliferation and expansion. Recently, high expectations have been raised about the epicardium as a candidate source of cells for the repair of the damaged heart. Because of its developmental importance and therapeutic potential, current research on this topic focuses on the complex signals that control epicardial biology. This review describes the signaling pathways involved in the different stages of epicardial development and discusses the potential of epicardial signals as targets for the development of therapies to repair the diseased heart. (Circ Res. 2011;109:1429-1442.)

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Section: Fibroblast Growth Factormentioning

confidence: 99%

Signaling During Epicardium and Coronary Vessel Development

Pérez‐Pomares

Pompa

2011

Circulation Research

128

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“…Microsurgical ablation of the proepicardium results in deficient formation of the epicardium, deficient coronary vasculature, and a severe growth defect of the compact layer myocardium called ''thin myocardium syndrome'' (41). Genetic ablation of several epicardial molecules not only affects the development of the epicardium and EPDCs but also causes remarkable growth defects of the compact layer myocardium (13,41,42). In the present study, we have found that epicardium-specific deficiency in ␤-catenin expression does not only disturb the development of EPDCs but additionally leads to hypoplasia of the compact layer myocardium and reduced expansion (ballooning) of the ventricles.…”

Section: Impaired Development Of Epdcs and Myocardial Growth Defectsmentioning

confidence: 99%

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

Zamora

Männer²,

Ruiz‐Lozano³

2007

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

156

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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“…In addition to the myocardial cell themselves, signals from the epicardium to the myocardium play an essential role in ventricular wall compact zone expansion (Kreidberg et al 1993;Kwee et al 1995;Yang et al 1995;Chen et al 2002;Pennisi et al 2003), while neither endocardium nor neural crest has been implicated. The phenotype observed for SMRT −/− embryos was strikingly similar to the heart phenotype reported previously for Retinoid X Receptor ␣ (RXR␣) gene-deleted mice (Kastner et al 1994;Sucov et al 1994) that has been reported to be independent of RXR␣ expression in myocytes (Chen et al 1998;Tran and Sucov 1998;Subbarayan et al 2000b) but to require RXR␣ in the epicardium .…”

Section: Smrt Is Required In Cardiac Myocardiummentioning

confidence: 99%

Cooperative regulation in development by SMRT and FOXP1

Jepsen¹,

Gleiberman²,

Shi³

et al. 2008

Genes Dev.

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A critical aspect of mammalian development involves the actions of dedicated repressors/corepressors to prevent unregulated gene activation programs that would initiate specific cell determination events. While the role of NCoR/SMRT corepressors in nuclear receptor actions is well documented, we here report that a previously unrecognized functional interaction between SMRT and a forkhead protein, FOXP1, is required for cardiac growth and regulation of macrophage differentiation. Our studies demonstrate that SMRT and FOXP1 define a functional biological unit required to orchestrate specific programs critical for mammalian organogenesis, linking developmental roles of FOX to a specific corepressor.Supplemental material is available at http://www.genesdev.org.Received November 27, 2007; revised version accepted January 18, 2008. Although activation of transcription has long been recognized as an essential component of gene regulation during development, the critical role of transcriptional repression programs is apparent from the pluripotent stem cell to terminal differentiation events. Nuclear receptors, including retinoic acid and thyroid hormone receptors (RAR and T 3 R), regulate development through both ligand-dependent activation and active repression by unliganded nuclear receptors (Glass and Rosenfeld 2000), and their ability to actively repress transcription in the absence of their cognate ligands is conferred by their interaction with SMRT or with the highly related corepressor NCoR (Chen and Evans 1995;Horlein et al. 1995). NCoR and SMRT also confer transcriptional repression to many additional members of the nuclear receptor superfamily, as well as on a variety of unrelated transcription factors, at least in part due to corecruitment of histone deacetylase proteins (HDACs) (Privalsky 2001;Jepsen and Rosenfeld 2002;Jones and Shi 2003).The forkhead family of transcription factors, which includes over a hundred genes in several species named for the forkhead-box (FOX) DNA-binding domain, has been characterized as both transcriptional activators and repressors (for review, see Wijchers et al. 2006). While all four FoxP family members function as transcriptional repressors, the mechanism of this repression remains largely uncharacterized, although FoxP3 has been shown to be capable of interacting with HDAC proteins (Li et al. 2007). Gene deletion studies have revealed that FOXP1 mutant mice have defects in cardiac morphogenesis, a thin ventricular myocardial compact zone, and lack of proper ventricular septation, which together result in embryonic death at embryonic day 14.5 (E14.5) (Wang et al. 2004). Interestingly, maintaining the proper balance of histone acetylation/deacetylation is critical for proper cardiac development and growth (Backs and Olson 2006;Montgomery et al. 2007), leading us to consider potential links between FOXP1 and recruitment of specific corepressor complexes.Here we report that deletion of the gene encoding the corepressor SMRT resulted in specific developmental abnormalities in...

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Epicardium is required for the full rate of myocyte proliferation and levels of expression of myocyte mitogenic factors FGF2 and its receptor, FGFR‐1, but not for transmural myocardial patterning in the embryonic chick heart

Cited by 98 publications

References 70 publications

Signaling During Epicardium and Coronary Vessel Development

Signaling During Epicardium and Coronary Vessel Development

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

Cooperative regulation in development by SMRT and FOXP1

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