Key Points
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Human mutations in Notch signalling components have been implicated in several forms of congenital cardiovascular disease, including cardiac outflow tract defects (jagged 1, notch 2), aortic valve disease (notch 1), cardiomyopathy (presenilin 1 and 2), and cerebral arteriopathy (notch 3).
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Emerging evidence shows that Notch has many distinct roles during cardiac development. The outcome of Notch signalling varies according to cell type and stage of development. Notch inhibits the differentiation of cardiomyocytes from mesoderm in embryos and embryonic stem cells.
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Notch and/or its target genes of the Hes-related transcription factor (Hrt) family are necessary for boundary formation in the developing atrioventricular canal.
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Notch promotes epithelial-to-mesenchymal transition in the developing heart valves by upregulating Snail and Slug expression, promoting the loss of adhesion proteins, and inducing the expression of mesenchymal markers.
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Notch activity in the endocardium promotes ventricular trabeculation by inducing the expression of ephrin B2 and bone morphogenetic protein 10 (BMP10), which promote the proliferation and differentiation of adjacent myocardial cells.
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Notch is required in cardiac neural crest cells for the specification of smooth muscle cell fate and for the proper morphogenesis of the cardiac outflow tract.
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Hrt genes are the best studied Notch targets in the heart; here they have crucial functions in cardiac morphogenesis by regulating chamber-specific gene expression, atrioventricular canal development and valve formation. However, some Hrt genes might be regulated in a Notch-independent manner.
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Not all Notch-related phenotypes can be explained by Hrt gene activity, indicating that additional unidentified Notch target genes might be essential for cardiac development.
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Understanding the functions of Notch in cardiac development has implications for understanding congenital and adult heart disease, and shows potential for developing new therapeutic strategies for heart failure and cardiac repair.
Abstract
Notch receptors and their cognate ligands transduce crucial signals between cells in various tissues, and have been conserved across millions of years of evolution. Mutations in Notch signalling components result in congenital heart defects in humans and mice, demonstrating an essential role for Notch in cardiovascular development. The results of recent experiments implicate this signalling pathway in many stages of heart development, and provide mechanistic insight into the vital functions of Notch in the aetiology of several common forms of paediatric and adult cardiac disease.
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Glossary
- Trabeculae
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Specialized sheets of myocardium forming protrusions that line the inside of the ventricles.
- Sarcomeric
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Pertaining to the sarcomere, the contractile unit composed of actin and myosin fibres within muscle cells.
- Hypocellular
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Having fewer cells than is seen in normal structures.
- Haploinsufficiency
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When loss of function of one gene copy leads to an abnormal phenotype.
- Bicuspid aortic valve
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An aortic valve that has only two leaflets instead of three. This congenital disorder often leads to valve calcification or degeneration with ageing.
- Aortic valve calcification
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Hardening of the aortic valve leaflets due to deposition of calcium-containing substances, which can result in a narrowing of the valve orifice or compromised valve function.
- Tetralogy of Fallot
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A congenital heart disorder characterized by a hole in the septum that normally separates the left and right ventricles, an abnormally located connection between the left ventricle and the aorta, a narrowed connection between the right ventricle and the pulmonary artery, and an enlarged right ventricle.
- Cell-autonomous
-
Describes a genetic trait in which only genotypically mutant cells show the mutant phenotype.
- Atresia
-
Failure to form a structure during development.
- Congestive heart failure
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The inability of the heart to pump enough blood to meet the demands of the body, resulting in elevated venous pressures and congestion of blood in the liver.
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High, F., Epstein, J. The multifaceted role of Notch in cardiac development and disease. Nat Rev Genet 9, 49–61 (2008). https://doi.org/10.1038/nrg2279
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DOI: https://doi.org/10.1038/nrg2279
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