title: BMP4 promotes EMT and mesodermal commitment in human embryonic stem cells via SLUG and MSX2.
abstract: Bone morphogenetic proteins (BMPs) initiate differentiation in human embryonic stem cells (hESCs) but the exact mechanisms have not been fully elucidated. We demonstrate here that SLUG and MSX2, transcription factors involved in epithelial-mesenchymal transitions, essential features of gastrulation in development and tumor progression, are important mediators of BMP4-induced differentiation in hESCs. Phosphorylated Smad1/5/8 colocalized with the SLUG protein at the edges of hESC colonies where differentiation takes place. The upregulation of the BMP target SLUG was direct as shown by the binding of phosphorylated Smad1/5/8 to its promoter, which interrupted the formation of adhesion proteins, resulting in migration. Knockdown of SLUG by short hairpin RNA blocked these changes, confirming an important role for SLUG in BMP-mediated mesodermal differentiation. Furthermore, BMP4-induced MSX2 expression leads to mesoderm formation and then preferential differentiation toward the cardiovascular lineage.
authors.affiliation: Department of Biochemistry and Molecular Biology, BioMedical Center, University of Iceland, Iceland.
authors.forename: Anne
authors.initials: A
authors.lastname: Richter
authors.forename: Lena
authors.initials: L
authors.lastname: Valdimarsdottir
authors.forename: Helga Eyja
authors.initials: HE
authors.lastname: Hrafnkelsdottir
authors.forename: Johann Frimann
authors.initials: JF
authors.lastname: Runarsson
authors.forename: Arna Run
authors.initials: AR
authors.lastname: Omarsdottir
authors.forename: Dorien
authors.initials: D
authors.lastname: Ward-van Oostwaard
authors.forename: Christine
authors.initials: C
authors.lastname: Mummery
authors.forename: Gudrun
authors.initials: G
authors.lastname: Valdimarsdottir
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D055415:Bone Morphogenetic Protein 4; D015820:Cadherins; D018398:Homeodomain Proteins; C084119:MSX2 protein; C000604407:SNAI1 protein, human; D051785:Smad Proteins; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors
keywords: BMP; EMT; Human ESCs; MSX2; Mesodermal differentiation; SLUG