title: A regulatory loop involving Dies1 and miR-125a controls BMP4 signaling in mouse embryonic stem cells.
abstract: Bone morphogenetic protein 4 (BMP4) plays an important role in maintaining embryonic stem cells (ESCs) in the undifferentiated state and in the regulation of lineage commitment. We recently identified a transmembrane protein, named Dies1, the suppression of which by RNA interference blocks mouse ESC differentiation by interfering with the BMP4 signaling. We asked whether modulation of Dies1 levels could be a physiological mechanism to regulate ESC pluripotency and/or differentiation. We demonstrated that miR-125a targets Dies1 and regulates its expression in ESCs. The overexpression of miR-125a impairs differentiation, and this effect is specifically mediated by Dies1 down-regulation and accompanied by a decrease of BMP4 signaling. We also found that Dies1 is associated with BMP4 receptor complex and that BMP4 activates the transcription of miR-125a gene. Therefore, a feedback loop exists that sets ESC sensitivity to BMP4. The analysis of this regulatory mechanism revealed that miR-125a overexpression and the consequent inhibition of the BMP4 signaling arrest the cells in the epiblast stem cell (epiSC) status, due to the concomitant activation of the Nodal/Activin pathway.
authors: Ceinge Biotecnologie Avanzate, Naples, Italy.
authors: Silvia
authors: S
authors: Parisi
authors: Marica
authors: M
authors: Battista
authors: Anna
authors: A
authors: Musto
authors: Angelica
authors: A
authors: Navarra
authors: Carolina
authors: C
authors: Tarantino
authors: Tommaso
authors: T
authors: Russo
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D016086:Lentivirus / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D055415:Bone Morphogenetic Protein 4; D008565:Membrane Proteins; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; C548983:Vsir protein, mouse; D000469:Alkaline Phosphatase