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Mol Cell Biol. 2017 Jan 19;37(3). pii: e00466-16. doi: 10.1128/MCB.00466-16. Print 2017 Feb 1.

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M.

Su CH1,2, Hung KY2, Hung SC2,3,4, Tarn WY5,2.

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Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Department of Orthopedics, Integrative Stem Cell Center, China Medical University Hospital, Taichung, Taiwan.
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan


RBM4 promotes differentiation of neuronal progenitor cells and neurite outgrowth of cultured neurons via its role in splicing regulation. In this study, we further explored the role of RBM4 in neuronal differentiation. During neuronal differentiation, energy production shifts from glycolysis to oxidative phosphorylation. We found that the splice isoform change of the metabolic enzyme pyruvate kinase M (PKM) from PKM2 to PKM1 occurs during brain development and is impaired in RBM4-deficient brains. The PKM isoform change could be recapitulated in human mesenchymal stem cells (MSCs) during neuronal induction. Using a PKM minigene, we demonstrated that RBM4 plays a direct role in regulating alternative splicing of PKM. Moreover, RBM4 antagonized the function of the splicing factor PTB and induced the expression of a PTB isoform with attenuated splicing activity in MSCs. Overexpression of RBM4 or PKM1 induced the expression of neuronal genes, increased the mitochondrial respiration capacity in MSCs, and, accordingly, promoted neuronal differentiation. Finally, we demonstrated that RBM4 is induced and is involved in the PKM splicing switch and neuronal gene expression during hypoxia-induced neuronal differentiation. Hence, RBM4 plays an important role in the PKM isoform switch and the change in mitochondrial energy production during neuronal differentiation.


alternative splicing; hypoxia; mesenchymal stem cells; neuronal differentiation; pyruvate kinase M

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