title: Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation.
abstract: 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.
authors.affiliation: University of California Comprehensive Cancer Center, San Francisco, California 94115, USA.
authors.forename: Luika A
authors.initials: LA
authors.lastname: Timmerman
authors.forename: Joaquín
authors.initials: J
authors.lastname: Grego-Bessa
authors.forename: Angel
authors.initials: A
authors.lastname: Raya
authors.forename: Esther
authors.initials: E
authors.lastname: Bertrán
authors.forename: José María
authors.initials: JM
authors.lastname: Pérez-Pomares
authors.forename: Juan
authors.initials: J
authors.lastname: Díez
authors.forename: Sergi
authors.initials: S
authors.lastname: Aranda
authors.forename: Sergio
authors.initials: S
authors.lastname: Palomo
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisúa-Belmonte
authors.forename: José Luis
authors.initials: JL
authors.lastname: de la Pompa
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000502:physiology; D005314:Embryonic and Fetal Development; D004847:Epithelial Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006321:Heart / Q000196:embryology*; D008565:Membrane Proteins / Q000235:genetics*; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D009924:Organ Culture Techniques; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics; D051880:Receptors, Notch; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish / Q000196:embryology
chemical_list: D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D051880:Receptors, Notch