title: miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis.
abstract: Numerous studies have indicated that BMP4 signaling is involved in the regulation of the early steps of development. In mouse embryonic stem cells (ESCs), BMP4 is crucial to sustain pluripotency and blocks differentiation towards neural fate. Here, through a systematic analysis of miRNAs in ESCs, we establish that BMP4 signaling regulates miR-23a, 27a and 24-2, through the recruitment of phospho-Smads at the promoter of the gene encoding this miRNA cluster. Suppression of miR-23a/b, 27a/b and 24 does not affect self-renewal or pluripotency, but induces an evident change of ESC differentiation, with a significant increase of the cells undergoing apoptosis after the transition from ESCs to epiblast stem cells (EpiSCs). BMP4 has been previously reported to cause apoptosis during ESC differentiation. By blocking BMP4 signaling, we completely prevent the apoptosis induced by suppression of the miRs. This suggests that the effects of miR suppression are the result of enhanced BMP4 signaling. This hypothesis is further supported by the observation that Smad5, the transcription factor downstream of the BMP4 receptor, is targeted by the miRNAs of the 23a and 23b clusters. Altogether, our results highlight the existence of a regulatory loop, involving Smad5 and the miR-23a clusters, that modulates the apoptotic response of ESCs to BMP4.
authors.affiliation: 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Via Sergio Pansini 5, Naples, Italy [2] Ceinge Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Musto
authors.affiliation: 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Via Sergio Pansini 5, Naples, Italy [2] Ceinge Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Navarra
authors.affiliation: 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Via Sergio Pansini 5, Naples, Italy [2] Ceinge Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Vocca
authors.affiliation: 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Via Sergio Pansini 5, Naples, Italy [2] Ceinge Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gargiulo
authors.affiliation: 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Via Sergio Pansini 5, Naples, Italy [2] Ceinge Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Minopoli
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Via Sergio Pansini 5, Naples, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Romano
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Via Sergio Pansini 5, Naples, Italy.
authors.forename: M F
authors.initials: MF
authors.lastname: Romano
authors.affiliation: 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Via Sergio Pansini 5, Naples, Italy [2] Ceinge Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Russo
authors.affiliation: 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Via Sergio Pansini 5, Naples, Italy [2] Ceinge Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Parisi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*
chemical_list: D055415:Bone Morphogenetic Protein 4; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; C529080:Mirn24 microRNA, mouse; C540674:Mirn27 microRNA, mouse