title: Mediator Med23 deficiency enhances neural differentiation of murine embryonic stem cells through modulating BMP signaling.
abstract: Unraveling the mechanisms underlying early neural differentiation of embryonic stem cells (ESCs) is crucial to developing cell-based therapies of neurodegenerative diseases. Neural fate acquisition is proposed to be controlled by a 'default' mechanism, for which the molecular regulation is not well understood. In this study, we investigated the functional roles of Mediator Med23 in pluripotency and lineage commitment of murine ESCs. Unexpectedly, we found that, despite the largely unchanged pluripotency and self-renewal of ESCs, Med23 depletion rendered the cells prone to neural differentiation in different differentiation assays. Knockdown of two other Mediator subunits, Med1 and Med15, did not alter the neural differentiation of ESCs. Med15 knockdown selectively inhibited endoderm differentiation, suggesting the specificity of cell fate control by distinctive Mediator subunits. Gene profiling revealed that Med23 depletion attenuated BMP signaling in ESCs. Mechanistically, MED23 modulated Bmp4 expression by controlling the activity of ETS1, which is involved in Bmp4 promoter-enhancer communication. Interestingly, med23 knockdown in zebrafish embryos also enhanced neural development at early embryogenesis, which could be reversed by co-injection of bmp4 mRNA. Taken together, our study reveals an intrinsic, restrictive role of MED23 in early neural development, thus providing new molecular insights for neural fate determination.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Wanqu
authors.initials: W
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Song
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Naihe
authors.initials: N
authors.lastname: Jing
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China gwang@sibcb.ac.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D017403:In Situ Hybridization; D056892:Mediator Complex / Q000172:deficiency*; D051379:Mice; D046228:Microarray Analysis; D019636:Neurodegenerative Diseases / Q000628:therapy*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019485:Bone Morphogenetic Proteins; C541034:Med23 protein, mouse; D056892:Mediator Complex
keywords: BMP signaling; ETS1; Embryonic stem cells; MED23; Mediator; Neural differentiation