miR-34b/c Regulates Wnt1 and Enhances Mesencephalic Dopaminergic Neuron Differentiation

Roberto De Gregorio, Salvatore Pulcrano, Claudia De Sanctis, Floriana Volpicelli, Ezia Guatteo, Lars von Oerthel, Emanuele Claudio Latagliata, Roberta Esposito, Rosa Maria Piscitelli, Carla Perrone-Capano, Valerio Costa, Dario Greco, Stefano Puglisi-Allegra, Marten P. Smidt, Umberto di Porzio, Massimiliano Caiazzo, Nicola Biagio Mercuri, Meng Li, Gian Carlo Bellenchi

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The differentiation of dopaminergic neurons requires concerted action of morphogens and transcription factors acting in a precise and well-defined time window. Very little is known about the potential role of microRNA in these events. By performing a microRNA-mRNA paired microarray screening, we identified miR-34b/c among the most upregulated microRNAs during dopaminergic differentiation. Interestingly, miR-34b/c modulates Wnt1 expression, promotes cell cycle exit, and induces dopaminergic differentiation. When combined with transcription factors ASCL1 and NURR1, miR-34b/c doubled the yield of transdifferentiated fibroblasts into dopaminergic neurons. Induced dopaminergic (iDA) cells synthesize dopamine and show spontaneous electrical activity, reversibly blocked by tetrodotoxin, consistent with the electrophysiological properties featured by brain dopaminergic neurons. Our findings point to a role for miR-34b/c in neuronal commitment and highlight the potential of exploiting its synergy with key transcription factors in enhancing in vitro generation of dopaminergic neurons. In this article, Bellenchi and colleagues show that the microRNA miR-34b/c is expressed in FACS-purified Pitx3-GFP + neurons and promotes dopaminergic differentiation by negative modulating Wnt1 and the downstream WNT signaling pathway. Induced dopaminergic cells, expressing miR-34b/c, synthesize dopamine and show the electrophysiological properties featured by brain dopaminergic neurons.

Original languageEnglish (US)
Pages (from-to)1237-1250
Number of pages14
JournalStem Cell Reports
Volume10
Issue number4
DOIs
StatePublished - Apr 10 2018

Keywords

  • Wnt pathway
  • Wnt1
  • dopamine
  • epiSC
  • mESC
  • miR34b/c
  • microRNA
  • reprogramming
  • transdifferentiation

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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