title: RUNX3 maintains the mesenchymal phenotype after termination of the Notch signal.
abstract: Notch is a critical mediator of endothelial-to-mesenchymal transition (EndMT) during cardiac cushion development. Slug, a transcriptional repressor that is a Notch target, is an important Notch effector of EndMT in the cardiac cushion. Here, we report that the runt-related transcription factor RUNX3 is a novel direct Notch target in the endothelium. Ectopic expression of RUNX3 in endothelium induces Slug expression and EndMT independent of Notch activation. Interestingly, RUNX3 physically interacts with CSL, the Notch-interacting partner in the nucleus, and induces Slug in a CSL-dependent, but Notch-independent manner. Although RUNX3 may not be required for the initial induction of Slug and EndMT by Notch, because RUNX3 has a much longer half-life than Slug, it sustains the expression of Slug thereby maintaining the mesenchymal phenotype. CSL binds to the Runx3 promoter in the atrioventricular canal in vivo, and inhibition of Notch reduces RUNX3 expression in the cardiac cushion of embryonic hearts. Taken together, our results suggest that induction of RUNX3 may be a mechanism to maintain Notch-transformed mesenchymal cells during heart development.
authors.affiliation: British Columbia Cancer Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: YangXin
authors.initials: Y
authors.lastname: Fu
authors.forename: Alex Chia Yu
authors.initials: AC
authors.lastname: Chang
authors.forename: Michèle
authors.initials: M
authors.lastname: Fournier
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.forename: Kyle
authors.initials: K
authors.lastname: Niessen
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
mesh_terms: D002460:Cell Line; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology; D004727:Endothelium / Q000196:embryology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006207:Half-Life; D006321:Heart / Q000196:embryology*; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D038081:Organogenesis / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D051880:Receptors, Notch; C493729:Runx3 protein, human; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors