Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation.

By L. Timmerman, Joaquín Grego-Bessa, Á. Raya, E. Bertran, J. Pérez-Pomares, J. Diez, Sergi Aranda, S. Palomo, F. McCormick, J. Izpisúa-Belmonte and 1 more. Genes & Development, 2004

1,001 citations recorded by the source corpus.

Epithelial-to-mesenchymal transition (EMT) is fundamental to both embryogenesis and tumor metastasis. The Notch intercellular signaling pathway regulates cell fate determination throughout metazoan evolution, and overexpression of activating alleles is oncogenic in mammals. Here we demonstrate that Notch activity promotes EMT during both cardiac development and oncogenic transformation via transcriptional induction of the Snail repressor, a potent and evolutionarily conserved mediator of EMT in many tissues and tumor types. In the embryonic heart, Notch functions via lateral induction to promote a selective transforming growth factor-beta (TGFbeta)-mediated EMT that leads to cellularization of developing cardiac valvular primordia. Embryos that lack Notch signaling elements exhibit severely attenuated cardiac snail expression, abnormal maintenance of intercellular endocardial adhesion complexes, and abortive endocardial EMT in vivo and in vitro. Accordingly, transient ectopic expression of activated Notch1 (N1IC) in zebrafish embryos leads to hypercellular cardiac valves, whereas Notch inhibition prevents valve development. Overexpression of N1IC in immortalized endothelial cells in vitro induces EMT accompanied by oncogenic transformation, with corresponding induction of snail and repression of VE-cadherin expression. Notch is expressed in embryonic regions where EMT occurs, suggesting an intimate and fundamental role for Notch, which may be reactivated during tumor metastasis.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/803c5ae3b4e49f48452a4ac3bb35ebda4d715d2f

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In Molecular Biology

1. M. Nieto
2. J. P. Thiery
3. R. Weinberg
4. Jormay Lim
5. E. Hay
6. Thomas Brabletz
7. D. Medici
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Citations in the corpus

• Epithelial-mesenchymal transitions in development and disease. (2009, background): “Snail1 represses VE-cadherin transcription and promotes EMT (Timmerman et al., 2004), and inactivation of Hey2 causes major congenital heart defects and inactivation of Hey1 and HeyL, suggesting that these two factors cooperate in EMT and that their combined inactivation induces ventricular septal…”
• TGF-β and epithelial-to-mesenchymal transitions (2005, background): “Interestingly, an opposite hierarchy of the two pathways is observed during mouse embryonic heart development, where Notch and its downstream target and constitutive transcriptional repressor RBP-Jk (CBF1) are required for the expression of TGF-b2 and TGF-b receptors and Oncogene for EMT of the endo”
• Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer (2016, background): “Other signaling pathways, including Notch [11], Wnt [10], Hedgehog [12],”
• The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it (2005, background): “There is overlap with Wnt pathways in the heart (Liebner et al., 2004), -Catenin is required for EMT in mammalian heart cushion EMT, whereas the Notch gene seems to be required for endocardial EMT (Timmerman et al., 2004).”
• The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. (2007, background): “Notch1 germline mutations disrupt normal development of the aortic valve, and occasionally of the mitral valve, often leading to a bicuspid aortic valve that may calcify in adulthood.(10) Notch and its ligand Jagged1 occur specifically in the ventricular outflow tract during endocardial cushion form”
• Epithelial-mesenchymal transitions: insights from development (2012, background): “In the second pathway, Notch promotes TGF2-induced EMT and induces the transcription of Snail1 (Timmerman et al., 2004).”
• Dynamic EMT: a multi‐tool for tumor progression (2021, positive): “In particular, EGF is cooperating with other signaling pathways, e.g., IL 6 R/STAT 3 and TGF b , resulting in CDH 1 downregulation and enhanced cell motility and invasion (Lo et al , 2007 ; Tian et al , 2007 ; Uttamsingh et al , 2008 ; Colomiere et al , 2009 ).”
• Adam10 is essential for early embryonic cardiovascular development (2010, methodology): “a RESEARCH ARTICLE Adam10 Is Essential for Early Embryonic”
• Complex networks orchestrate epithelial–mesenchymal transitions (2006, background): “Analysis of RBPJk and NOTCH1 mutant embryos indicated that NOTCH-induced TGFβ2 transcription regulates the endocardial EMT that is required for cardiac-valve developmen”
• Zebrafish as a model to study cardiac development and human cardiac disease (2011, result): “Recent studies employing live high-speed imaging using single-plane illumination microscopy revealed that although the endocardial cells form a multicellular cushion structure, these endocardial cells remain epithelial and do not delaminate in the manner described for endocardial cushion cells in th”
• Notch signaling: simplicity in design, versatility in function (2011, background): “TGF-mediated epithelial-tomesenchymal transition (EMT) also requires functional Notch signaling in the developing heart (Timmerman et al., 2004) and in various epithelia (Niimi et al., 2007; Zavadil et al., 2004).”
• The developmental genetics of congenital heart disease (2008, background): “NOTCH1 is expressed in the endocardium of the great vessels of the heart, where it is thought to be important for epithelial-to-mesenchymal transition and valve formatio”
• Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition (2010, background): “, the critical signals mediating both EMT and stemnes”