title: Snail promotes the cell-autonomous generation of Flk1(+) endothelial cells through the repression of the microRNA-200 family.
abstract: Expression of the transcription factor Snail is required for normal vasculogenesis in the developing mouse embryo. In addition, tumors expressing Snail have been associated with a more malignant phenotype, with both increased invasive properties and angiogenesis. Although the relationship between Snail and vasculogenesis has been noted, no mechanistic analysis has been elucidated. Here, we show that in addition to inducing an epithelial mesenchymal transition, Snail promotes the cell-autonomous induction of Flk1(+) endothelial cells in an early subset of differentiating mouse embryonic stem (ES) cells. Cells that become Flk1+ in response to Snail have a transcriptional profile specific to Gata6+primitive endoderm, but not the early Nanog+epiblast. We further show that Snail's ability to promote Flk1(+) endothelium depends on fibroblast growth factor signaling as well as the repression of the microRNA-200 (miR-200) family, which directly targets the 3' UTRs of Flk1 and Ets1. Together, our results show that Snail is capable of inducing Flk1+ lineage commitment in a subset of differentiating ES cells through the down-regulation of the miR-200 family. We hypothesize that this mechanism of Snail-induced vasculogenesis may be conserved in both the early developing embryo and malignant cancers.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Gill
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Langer
authors.forename: R Coleman
authors.initials: RC
authors.lastname: Lindsley
authors.forename: Mi
authors.initials: M
authors.lastname: Cai
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Murphy
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D005855:Germ Layers / Q000098:blood supply / Q000196:embryology / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D015398:Signal Transduction / Q000235:genetics*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D050993:GATA6 Transcription Factor; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D008156:Luciferases; D040301:Vascular Endothelial Growth Factor Receptor-2