Epithelial-mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor β

Potts, Jay D.; Runyan, Raymond B.

doi:10.1016/0012-1606(89)90111-5

Cited by 270 publications

(174 citation statements)

References 22 publications

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“…The three mammalian TGF␤ isoforms have distinct but overlapping expression patterns in the mouse embryo that change as development progresses Pelton et al, 1991). TGF␤1 mRNA is expressed in the cardiac mesoderm and endocardial tube of the presomite mouse embryo Dickson et al, 1993) and becomes restricted with development to cells overlying the endocardial cushions , where it is thought to induce endothelial-tomesenchymal transformation (Potts and Runyan, 1989). TGF␤1 protein is not present in presomite embryos but is expressed in the mouse heart on E8.5-E16.5 (Montengua et al, 1998), and it declines to barely detectable levels by E17.5 (Pelton et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia‐induced TGFβ and fibronectin expression in embryonic mouse heart

Smoak

2004

Developmental Dynamics

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Cardiovascular defects are common in diabetic offspring, but their etiology and pathogenesis are poorly understood. Extracellular matrix accumulates in adult tissues in response to hyperglycemia, and transforming growth factor-beta1 (TGF␤1) likely mediates this effect. The objective of this study was to characterize TGF␤ expression in the organogenesisstage mouse heart and to evaluate TGF␤ and fibronectin expression in embryonic mouse heart exposed to hyperglycemia. Prominent TGF␤1, and minimal TGF␤2 or TGF␤3, protein expression was demonstrated in embryonic day (E) 9.5-E13.5 hearts. Hyperglycemia for 24 hr produced significantly increased fibronectin, slightly increased TGF␤1, and unchanged TGF␤2 or TGF␤3, by immunohistochemistry. Increased TGF␤1 was demonstrated by enzyme-linked immunosorbent assay in embryonic fluid and isolated hearts after hyperglycemia for 24 hr, but not 48 hr. Hyperglycemia increased fibronectin protein and mRNA expression in embryonic hearts after 24 hr, and pericardial injection of TGF␤1 also increased fibronectin mRNA in the embryonic heart. It is proposed that TGF␤1 and fibronectin may play a role in diabetes-induced cardiac dysmorphogenesis.

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Section: Discussionmentioning

confidence: 99%

Hyperglycemia‐induced TGFβ and fibronectin expression in embryonic mouse heart

Smoak

2004

Developmental Dynamics

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“…The functional importance of the myocardium on EMT has also been emphasized by in vitro experiments studying the effect of Tgf␤2 on endocardial cells in the chicken and mouse (Boyer and Runyan, 2001a;Camenisch et al, 2002). Furthermore, an additional effect of the myocardium has been suggested as in the absence of myocyte-conditioned medium, the addition of Tgf␤2 resulted in loss of cell-cell adhesion and cellular hypertrophy but failed to induce mesenchyme formation (Potts and Runyan, 1989;Nakajima et al, 1998). Cardiac looping has also been developmentally linked to the correct placement and fusion of the endocardial cushions (Eisenberg and Markwald, 1995), which express Tgf␤2 as well.…”

Section: Myocardiummentioning

confidence: 99%

Expression patterns of Tgfβ1–3 associate with myocardialisation of the outflow tract and the development of the epicardium and the fibrous heart skeleton

Molin

Bartram

Heiden

et al. 2003

Developmental Dynamics

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Transforming growth factor-beta (Tgf␤) is essential for normal embryogenesis. The cardiac phenotypes obtained after knockout of each of the three mammalian isoforms suggest different roles during morphogenesis. We studied cardiovascular expression of Tgf␤1-3 in parallel tissue sections of normal mouse embryos from 9.5 to 15.5 days post coitum (dpc) by using radioactive in situ hybridisation. The Tgf␤ isoforms are differentially expressed in unique and in overlapping patterns during cardiovascular development. In the vessels, Tgf␤1 is found in the intima, whereas Tgf␤2 and -␤3 are mainly present in the media and adventitia of the great arteries. Tgf␤1 is present in the endocardium at all stages examined. The Tgf␤2 signal in the endocardium of the atrioventricular canal and outflow tract (9.5 dpc) shifts during epithelial-mesenchymal transformation toward the mesenchymal cushions (10.5-11.5 dpc) after which it exhibits a marked spatiotemporal expression pattern as the cushion differentiation progresses (11.5-15.5 dpc). The myocardium underlying the endocardial cushions and the atrial muscular septum are intensely positive for Tgf␤2 at early stages (9.5-11.5 dpc) and expression decreases at 12.5 days. In contrast to earlier reports, we find marked overlap of Tgf␤2 and -␤3 expression. Tgf␤3 expression shows a characteristic distribution in the mesenchymal cushions, suggesting a role in cushion differentiation, possibly additional to Tgf␤2. From 14.5 dpc onward, a strong Tgf␤3 signal is found in the fibrous septum primum of the atrium and in the fibrous skeleton of the heart. Special attention was paid to the proepicardial organ and its derivatives. The proepicardial organ strongly expresses Tgf␤2 as early as 9.5 days, and all isoforms are present in the epicardium from 12.5 dpc onward. The spatiotemporal cardiovascular expression of Tgf␤1-3 supports both specific and complementary functions during cardiovascular development that might explain functional redundancy between the Tgf␤-isoforms. The information provided favors novel roles of Tgf␤1-3 in epicardial development, of Tgf␤2 in myocardialisation, and of Tgf␤3 in differentiation of the fibrous structures of the heart. Developmental Dynamics 227: 431-444, 2003.

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“…During cushion formation, TGFβ signalling promotes EMT and mesenchymal invasiveness [19,70]. TGFβ1 is initially expressed in the endocardium (E8.0) and becomes restricted to AVC endocardium at E9.5, when EMT takes place and is sustained in endocardial cells of cardiac valves until just after birth [71].…”

Section: Tgfβ Signalling In Cardiac Valve Developmentmentioning

confidence: 99%

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

Garside

Chang

Karsan

et al. 2012

Cell. Mol. Life Sci.

131

123

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Congenital heart defects affect approximately 1-5% of human newborns each year and of these cardiac defects, 20-30% are due to heart valve abnormalities. Recent literature indicates that key factors and pathways that regulate valve development are also implicated in congenital heart defects and valve disease. Currently, there are limited options for treatment of valve disease and therefore, having a better understanding of valve development can contribute critical insight into congenital valve defects and disease. There are three major signalling pathways required for early specification and initiation of Endothelial-to-Mesenchymal Transformation (EMT) in the cardiac cushions: BMP, TGFβ, and Notch signalling. BMPs secreted from the myocardium setup the environment for the overlying endocardium to become activated, Notch signalling initiates EMT, and both BMP and TGFβ signalling synergizes with Notch to promote the transition of endothelia to mesenchyme and to promote mesenchymal cell invasiveness. Together, these three essential signalling pathways help to form the cardiac cushions and populate them with mesenchyme and, consequently, set off the cascade of events required to develop mature heart valves. Furthermore, integration and cross-talk between these pathways generate highly stratified and delicate valve leaflets and septa of the heart. Here, we discuss BMP, TGFβ, and Notch signalling pathways during mouse cardiac cushion formation and how they together produce a coordinated EMT response in the developing mouse valves.

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Epithelial-mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor β

Cited by 270 publications

References 22 publications

Hyperglycemia‐induced TGFβ and fibronectin expression in embryonic mouse heart

Hyperglycemia‐induced TGFβ and fibronectin expression in embryonic mouse heart

Expression patterns of Tgfβ1–3 associate with myocardialisation of the outflow tract and the development of the epicardium and the fibrous heart skeleton

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

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