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Nat Commun. 2017 Mar 30;8:14741. doi: 10.1038/ncomms14741.

FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons.

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Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome 00161, Italy.
Deparment of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, New York, New York 10032, USA.
Institute of Molecular Biology and Pathology, CNR, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.


The RNA-binding protein FUS participates in several RNA biosynthetic processes and has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Here we report that FUS controls back-splicing reactions leading to circular RNA (circRNA) production. We identified circRNAs expressed in in vitro-derived mouse motor neurons (MNs) and determined that the production of a considerable number of these circRNAs is regulated by FUS. Using RNAi and overexpression of wild-type and ALS-associated FUS mutants, we directly correlate the modulation of circRNA biogenesis with alteration of FUS nuclear levels and with putative toxic gain of function activities. We also demonstrate that FUS regulates circRNA biogenesis by binding the introns flanking the back-splicing junctions and that this control can be reproduced with artificial constructs. Most circRNAs are conserved in humans and specific ones are deregulated in human-induced pluripotent stem cell-derived MNs carrying the FUSP525L mutation associated with ALS.

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