Notch Signaling Is Essential for Ventricular Chamber Development

Grego-Bessa, Joaquím; Luna-Zurita, Luis; Monte, Gonzalo del; Bolós, Victoria; Melgar, Pedro; Arandilla, Alejandro; Garratt, Alistair N.; Zang, Heesuk; Mukouyama, Yoh‐suke; Chen, Hanying; Shou, Weinian; Ballestar, Esteban; Esteller, Manel; Rojas, Ana M.; Pérez‐Pomares, José M.; Pompa, José Luis de la

doi:10.1016/j.devcel.2006.12.011

Cited by 445 publications

(548 citation statements)

References 52 publications

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“…S5). These defects are very similar to the phenotypes of Notch1 and Notch target RBPJk knockout mice (Timmerman et al, 2004;Limbourg et al, 2005;Grego-Bessa et al, 2007), supporting the idea that ADAM10 plays an essential role in the Notch pathway in regulating cardiac development.…”

Section: Impaired Emt and Ventricular Trabeculation In The Heart Of Asupporting

confidence: 70%

“…Our investigation of Adam10 endothelial knockout mouse model explicitly demonstrates that Adam10 is essential for endocardial cushion formation, ventricular trabeculation, and vasculogenesis. The AEKO mice not only phenocopied the Notch1 and Notch targets knockouts (Krebs et al, 2000;Fischer et al, 2004;Timmerman et al, 2004;Limbourg et al, 2005;Grego-Bessa et al, 2007), but also showed downregulated expression of Notch target gene Snail and Bmp2 in the cardiac tissues. Because we delete Adam10 primarily in the endothelial cells, which are only small fraction of the total cardiac, the expression changes of Snail and Bmp2 could be more severe in Adam10 deficient endocardium.…”

Section: Discussionmentioning

confidence: 99%

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Adam10 is essential for early embryonic cardiovascular development

Zhang

Tian

Chi

et al. 2010

Developmental Dynamics

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Notch pathway has been demonstrated to regulate cardiovascular development. One important step in Notch pathway is the cleavage of Notch receptor, during which an intracellular fragment of Notch protein is released to activate downstream genes. It is still uncertain whether Adam10, the mammalian homologue of Kuzbanian in Drosophila, is required to activate the Notch pathway during cardiovascular development. To further understand the physiological function of Adam10 in vascular and cardiac development, we generated mice lacking the Adam10 gene primarily in the endothelial compartment. We found that disruption of Adam10 in endothelial cells resulted in embryonic death after embryonic day 10.5 due to multiple cardiac and vascular defects similar to Notch1 mutants. We further showed that the expression of Notch target genes Snail and Bmp2 are impaired in Adam10‐deficient cardiac tissues. Finally, we provide experimental evidence to support that Adam10 functions in a cell autonomous manner during mammalian cardiac development. Developmental Dynamics 239:2594–2602, 2010. © 2010 Wiley‐Liss, Inc.

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Section: Impaired Emt and Ventricular Trabeculation In The Heart Of Asupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Adam10 is essential for early embryonic cardiovascular development

Zhang

Tian

Chi

et al. 2010

Developmental Dynamics

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“…Loss of Bmp10 results in ventricular trabeculation defect due to decreased cardiomyocyte proliferation. Ablation of NOTCH signaling causes reduced Bmp10 expression and cardiomyocyte proliferation in the heart (36). Based on RNA in situ hybridization, there was no difference in Bmp10 expression in the trabeculae of the Zfp57 −/+ (M − Z + ) and −/− mz (M − Z − ) E10.5 embryos (SI Appendix, Fig.…”

Section: Notch Signaling Pathway Was Perturbed In the Heart Of Zfp57mentioning

confidence: 99%

“…Ablation of NOTCH signaling causes reduced BMP10 signaling and decreased cardiomyocyte proliferation (36). To determine if cardiomyocyte proliferation was reduced without ZFP57, we performed EdU incorporation assay in the heart of E13.5 embryos (Fig.…”

Section: Notch Signaling Pathway Was Perturbed In the Heart Of Zfp57mentioning

confidence: 99%

Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development

Shamis

Cullen²,

Liu

et al. 2015

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

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Zfp57 is a maternal–zygotic effect gene that maintains genomic imprinting. Here we report that Zfp57 mutants exhibited a variety of cardiac defects including atrial septal defect (ASD), ventricular septal defect (VSD), thin myocardium, and reduced trabeculation. Zfp57 maternal-zygotic mutant embryos displayed more severe phenotypes with higher penetrance than the zygotic ones. Cardiac progenitor cells exhibited proliferation and differentiation defects in Zfp57 mutants. ZFP57 is a master regulator of genomic imprinting, so the DNA methylation imprint was lost in embryonic heart without ZFP57. Interestingly, the presence of imprinted DLK1, a target of ZFP57, correlated with NOTCH1 activation in cardiac cells. These results suggest that ZFP57 may modulate NOTCH signaling during cardiac development. Indeed, loss of ZFP57 caused loss of NOTCH1 activation in embryonic heart with more severe loss observed in the maternal-zygotic mutant. Maternal and zygotic functions of Zfp57 appear to play redundant roles in NOTCH1 activation and cardiomyocyte differentiation. This serves as an example of a maternal effect that can influence mammalian organ development. It also links genomic imprinting to NOTCH signaling and particular developmental functions.

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“…Loss of Notch1 leads to defects in angiogenesis, loss of cellularization in the AVC, blocked ventricular trabeculation, and disrupted vasculature resulting in embryonic lethality at E10.5 similar to Rbpj null mice [144,156,157]. Notch1 −/− mice have collapsed endocardium and lack cushion mesenchyme at the onset of valve formation, indicating that Notch1 is required for EMT [144].…”

Section: Notch 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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Notch Signaling Is Essential for Ventricular Chamber Development

Cited by 445 publications

References 52 publications

Adam10 is essential for early embryonic cardiovascular development

Adam10 is essential for early embryonic cardiovascular development

Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development

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

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