Coordinating Tissue Interactions: Notch Signaling in Cardiac Development and Disease

Program of Cardiovascular Developmental Biology, Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
Developmental Cell (Impact Factor: 9.71). 02/2012; 22(2):244-54. DOI: 10.1016/j.devcel.2012.01.014
Source: PubMed


The Notch pathway is a crucial cell-fate regulator in the developing heart. Attention in the past centered on Notch function in cardiomyocytes. However, recent advances demonstrate that region-specific endocardial Notch activity orchestrates the patterning and morphogenesis of cardiac chambers and valves through regulatory interaction with multiple myocardial and neural crest signals. Notch also regulates cardiomyocyte proliferation and differentiation during ventricular chamber development and is required for coronary vessel specification. Here, we review these data and highlight disease connections, including evidence that Notch-Hey-Bmp2 interplay impacts adult heart valve disease and that Notch contributes to cardiac arrhythmia and pre-excitation syndromes.

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    • "These genes are critical components of the NOTCH signaling pathway, which regulates various developmental processes. This pathway is involved in the morphogenesis of the heart and the partitioning of the heart by the left-right axis[14]. Ninety percent of individuals with this condition exhibit phenotypes characteristic of peripheral pulmonary hypoplasia, pulmonary stenosis, and TOF[15].: Macro-deletion syndromes, such as 3q, 4q, 5p, 8p, 9p, 11q, 13q, 18p, and 18q, are commonly associated with congenital heart defects. "
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    ABSTRACT: Congenital heart defects (CHDs) represent the biggest fraction of morbid congenital anomalies worldwide. Owing to their complex inheritance patterns and multifactorial etiologies, these defects are difficult to identify before complete manifestation. Research over the past two decades has established firmly the role of genetics in the development of these congenital defects. While syndromic CHDs are more straightforward, non-syndromic CHDs are usually characterized by multiple mutations that affect intricate inter-connected developmental pathways. Knock-out and gene expression studies in mice and other genetic models have been performed to elucidate the roles of these implicated genes. Functional analysis has not been able to resolve the complete picture, as increasingly more downstream effects are continuously being assigned to CHD mutant factors. NKX2-5, a cardiac transcription factor, has received much attention for its role in cardiac dysmorphogenesis. Approximately 50 different mutations in this gene have been identified to date, and only a few have been functionally characterized. The mutant NKX2-5 factor can regulate a number of off-targets downstream to facilitate CHD development. This review summarizes the genetic etiology of congenital heart defects and emphasizes the need for NKX2-5 mutation screening.
    Preview · Article · Jan 2016 · Genes
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    • "They are usually associated with genetic mutations in genes essential for heart valve development. Notch signaling, for example, is necessary for the correct patterning of the heart chambers and the valve-forming endocardium [28]. By restricting Bmp2 expression to the atrioventricular canal (AVC) myocardium, as well as being expressed itself in the endocardial cells (EdCs), Notch regulates the epithelial-to-mesenchymal transition (EMT) process necessary for the formation of cardiac cushions in the mouse [95]. "
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    ABSTRACT: Mechanical forces are instrumental to cardiovascular development and physiology. The heart beats approximately 2.6 billion times in a human lifetime and heart valves ensure these contractions result in an efficient, unidirectional flow of the blood. Composed of endocardial cells (EdCs) and extracellular matrix (ECM), cardiac valves are among the most mechanically challenged structures of the body both during and after their development. Understanding how hemodynamic forces modulate cardiovascular function and morphogenesis is key to unravelling the relationship between normal and pathological cardiovascular development and physiology. Most valve diseases have their origins in embryogenesis, either as signs of abnormal developmental processes or the aberrant re-expression of fetal gene programs normally quiescent in adulthood. Here we review recent discoveries in the mechanobiology of cardiac valve development and introduce the latest technologies being developed in the zebrafish, including live cell imaging and optical technologies, as well as modeling approaches that are currently transforming this field. This article is part of a Special Issue entitled:Cardiomyocyte Biology: Integration of Develomental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
    Full-text · Article · Nov 2015 · Biochimica et Biophysica Acta
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    • "DEVELOPMENTAL DYNAMICS 244:31–42, 2015 DOI: 10.1002/DVDY.24216 causes EndMT defects and cushion hypoplasia (Timmerman et al., 2004; de la Pompa and Epstein, 2012; Hofmann et al., 2012). In addition, calcineurin signaling and its downstream transcription factors of the NFATc (nuclear factor of activated T cells, cytoplasmic , calcineurin dependent) family are implicated in EndMT during early cushion formation as well as in subsequent valvulogenesis (de la Pompa et al., 1998; Ranger et al., 1998; Crabtree and Olson, 2002; Chang et al., 2004; Combs and Yutzey, 2009b; Wu et al., 2011). "
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    ABSTRACT: Background: Endothelial-mesenchymal transformation (EndMT) is essential for endocardial cushion formation during cardiac morphogenesis. We recently identified Tmem100 as an endothelial gene indispensable for vascular development. In this study, we further investigated its roles for EndMT during atrioventricular canal (AVC) cushion formation. Results: Tmem100 was expressed in AVC endocardial cells, and Tmem100 null embryos showed severe EndMT defect in the AVC cushions. While calcineurin-dependent suppression of vascular endothelial growth factor (VEGF) expression in the AVC myocardium is important for EndMT, significant up-regulation of Vegfa expression was observed in Tmem100 null heart. EndMT impaired in Tmem100 null AVC explants was partially but significantly restored by the expression of constitutively-active calcineurin A, suggesting dysregulation of myocardial calcineurin-VEGF signaling in Tmem100 null heart. Moreover, Tmem100 null endocardial cells in explant culture did not show EndMT in response to the treatment with myocardium-derived growth factors, transforming growth factor β2 and bone morphogenetic protein 2, indicating involvement of an additional endocardial-specific abnormality in the mechanism of EndMT defect. The lack of NFATc1 nuclear translocation in endocardial cells of Tmem100 null embryos suggests impairment of endocardial calcium signaling. Conclusions: The Tmem100 deficiency causes EndMT defect during AVC cushion formation possibly via disturbance of multiple calcium-related signaling events.
    Preview · Article · Jan 2015 · Developmental Dynamics
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