Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation.
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.
Timmerman
Luika A
LA
University of California Comprehensive Cancer Center, San Francisco, California 94115, USA.
Grego-Bessa
Joaquín
J
Raya
Angel
A
Bertrán
Esther
E
Pérez-Pomares
José María
JM
Díez
Juan
J
Aranda
Sergi
S
Palomo
Sergio
S
McCormick
Frank
F
Izpisúa-Belmonte
Juan Carlos
JC
de la Pompa
José Luis
JL
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
D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D051880:Receptors, Notch