TY - JOUR
T1 - miR-34b/c Regulates Wnt1 and Enhances Mesencephalic Dopaminergic Neuron Differentiation
AU - De Gregorio, Roberto
AU - Pulcrano, Salvatore
AU - De Sanctis, Claudia
AU - Volpicelli, Floriana
AU - Guatteo, Ezia
AU - von Oerthel, Lars
AU - Latagliata, Emanuele Claudio
AU - Esposito, Roberta
AU - Piscitelli, Rosa Maria
AU - Perrone-Capano, Carla
AU - Costa, Valerio
AU - Greco, Dario
AU - Puglisi-Allegra, Stefano
AU - Smidt, Marten P.
AU - di Porzio, Umberto
AU - Caiazzo, Massimiliano
AU - Mercuri, Nicola Biagio
AU - Li, Meng
AU - Bellenchi, Gian Carlo
N1 - Funding Information:
We thank FIRB-RBIN062YH4, MERIT-RBNE08LN4P-002, PRIN 2015R9ASHT_003, and Finanziamento Ricerca di Ateneo to C.P.C. for financial support. We also thank Sara Mancinelli who provided the Tet-O-FUW-Ires-GFP empty vector and Dr. Antonio Simeone for anti-LMX1B antibody. We are grateful to the FACS facility and the Integrated Microscopy Facility of the Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” CNR, Naples, Italy.
Publisher Copyright:
© 2018 The Authors
PY - 2018/4/10
Y1 - 2018/4/10
N2 - 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.
AB - 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.
KW - Wnt pathway
KW - Wnt1
KW - dopamine
KW - epiSC
KW - mESC
KW - miR34b/c
KW - microRNA
KW - reprogramming
KW - transdifferentiation
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U2 - 10.1016/j.stemcr.2018.02.006
DO - 10.1016/j.stemcr.2018.02.006
M3 - Article
C2 - 29526736
AN - SCOPUS:85042906705
SN - 2213-6711
VL - 10
SP - 1237
EP - 1250
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 4
ER -