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      MicroRNA-145 Regulates Neural Stem Cell Differentiation Through the Sox2-Lin28/let-7 Signaling Pathway.

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          Abstract

          MicroRNAs (miRNAs or miRs) regulate several biological functions, including cell fate determination and differentiation. Although miR-145 has already been described to regulate glioma development, its precise role in neurogenesis has never been addressed. miR-145 represses sex-determining region Y-box 2 (Sox2), a core transcription factor of embryonic stem cells (ESCs), to inhibit pluripotency and self-renewal in human ESCs. In addition, the Sox2-Lin28/let-7 signaling pathway regulates proliferation and neurogenesis of neural precursors. In this study, we aimed to investigate the precise role of miR-145 in neural stem cell (NSC) fate decision, and the possible involvement of the Sox2-Lin28/let-7 signaling pathway in miR-145 regulatory network. Our results show for the first time that miR-145 expression significantly increased after induction of mouse NSC differentiation, remaining elevated throughout this process. Forced miR-145 downregulation decreased neuronal markers, namely βIII-tubulin, NeuN, and MAP2. Interestingly, throughout NSC differentiation, protein levels of Sox2 and Lin28, a well-known suppressor of let-7 biogenesis, decreased. Of note, neuronal differentiation also resulted in let-7a and let-7b upregulation. Transfection of NSCs with anti-miR-145, in turn, increased both Sox2 and Lin28 protein levels, while decreasing both let-7a and let-7b. More importantly, Sox2 and Lin28 silencing partially rescued the impairment of neuronal differentiation induced by miR-145 downregulation. In conclusion, our results demonstrate a novel role for miR-145 during NSC differentiation, where miR-145 modulation of Sox2-Lin28/let-7 network is crucial for neurogenesis progression. Stem Cells 2016;34:1386-1395.

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          Author and article information

          Journal
          Stem Cells
          Stem cells (Dayton, Ohio)
          Wiley-Blackwell
          1549-4918
          1066-5099
          May 2016
          : 34
          : 5
          Affiliations
          [1 ] Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
          [2 ] Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
          Article
          10.1002/stem.2309
          26849971
          7b4197f3-48a0-4bb7-9d8c-c0fde2971be5
          History

          Lin28,Neural stem cells,Neurogenesis,Sox2,let-7,miR-145
          Lin28, Neural stem cells, Neurogenesis, Sox2, let-7, miR-145

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