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RESEARCH PAPER
1 University of California Comprehensive Cancer Center, San Francisco, California 94115, USA , 2 Departamento de Oncología Molecular, Institut de Recerca Oncologica (IRO), Hospital Duran i Reynals, Barcelona, Spain , 3 Gene Expression Laboratories, The Salk Institute for Biological Studies, La Jolla, California 92037-1099, USA , 4 Departamento de Biología Animal, Facultad de Ciencias, Universidad de Málaga, 29071 Málaga, Spain
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-
(TGF)-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.
[Keywords: Notch; endocardium; lateral induction; EMT; snail; TGF]
Received June 24, 2003; revised version accepted November 18, 2003.
Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.276304.
6 These authors contributed equally to this work.
5 Present address: Departamento de Immunología y Oncología, Centro Nacional de Biotecnología-CSIC, Universidad Autónoma de Madrid, Campus Cantoblanco, 28049 Madrid, Spain.
E-MAIL jlpompa{at}cnb.uam.es; FAX 34-91-3720493.
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