title: Thymosin beta 4 up-regulates miR-200a expression and induces differentiation and survival of rat brain progenitor cells.
abstract: Thymosin beta 4 (Tβ4), a secreted 43 amino acid peptide, promotes oligodendrogenesis, and improves neurological outcome in rat models of neurologic injury. We demonstrated that exogenous Tβ4 treatment up-regulated the expression of the miR-200a in vitro in rat brain progenitor cells and in vivo in the peri-infarct area of rats subjected to middle cerebral artery occlusion (MCAO). The up-regulation of miR-200a down-regulated the expression of the following targets in vitro and in vivo models: (i) growth factor receptor-bound protein 2 (Grb2), an adaptor protein involved in epidermal growth factor receptor (EGFR)/Grb2/Ras/MEK/ERK1/c-Jun signaling pathway, which negatively regulates the expression of myelin basic protein (MBP), a marker of mature oligodendrocyte; (ii) ERRFI-1/Mig-6, an endogenous potent kinase inhibitor of EGFR, which resulted in activation/phosphorylation of EGFR; (iii) friend of GATA 2, and phosphatase and tensin homolog deleted in chromosome 10 (PTEN), which are potent inhibitors of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway, and resulted in marked activation of AKT; and (iv) transcription factor, p53, which induces pro-apoptotic genes, and possibly reduced apoptosis of the progenitor cells subjected to oxygen glucose deprivation (OGD). Anti-miR-200a transfection reversed all the effects of Tβ4 treatment in vitro. Thus, Tβ4 up-regulated MBP synthesis, and inhibited OGD-induced apoptosis in a novel miR-200a dependent EGFR signaling pathway. Our findings of miR-200a-mediated protection of progenitor cells may provide a new therapeutic importance for the treatment of neurologic injury. Tβ4-induced micro-RNA-200a (miR-200a) regulates EGFR signaling pathways for MBP synthesis and apoptosis: up-regulation of miR-200a after Tβ4 treatment, increases MBP synthesis after targeting Grb2 and thereby inactivating c-Jun from inhibition of MBP synthesis; and also inhibits OGD-mediated apoptosis after targeting EGFR inhibitor (Mig-6), PI3K inhibitors (FOG2 and Pten) and an inducer (p53) of pro-apoptotic genes, for AKT activation and down-regulation of p53. These findings may contribute the therapeutic benefits for stroke and other neuronal diseases associated with demyelination disorders.
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Santra
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, Michigan, USA.|Department of Physics, Oakland University, Rochester, Michigan, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Sutapa
authors.initials: S
authors.lastname: Santra
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Nallani
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Shivam
authors.initials: S
authors.lastname: Vyas
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
authors.affiliation: Department of Emergency Medicine, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Morris
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D013947:Thymosin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D000099201:Thymosin beta(4)
chemical_list: D035683:MicroRNAs; D013947:Thymosin; D000099201:Thymosin beta(4); C555600:MIRN200 microRNA, rat
keywords: AKT; epidermal growth; microRNA; myelin basic protein; progenitor cells; thymosin beta 4