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

Lorenzo Errichelli, Stefano Dini Modigliani, Pietro Laneve, Alessio Colantoni, Ivano Legnini, Davide Capauto, Alessandro Rosa, Riccardo De Santis, Rebecca Scarfò, Giovanna Peruzzi, Lei Lu, Elisa Caffarelli, Neil A. Shneider, Mariangela Morlando () and Irene Bozzoni ()
Additional contact information
Lorenzo Errichelli: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia
Stefano Dini Modigliani: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia
Pietro Laneve: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia
Alessio Colantoni: Deparment of Biology and Biotechnology ‘Charles Darwin’, Sapienza University of Rome
Ivano Legnini: Deparment of Biology and Biotechnology ‘Charles Darwin’, Sapienza University of Rome
Davide Capauto: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia
Alessandro Rosa: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia
Riccardo De Santis: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia
Rebecca Scarfò: Deparment of Biology and Biotechnology ‘Charles Darwin’, Sapienza University of Rome
Giovanna Peruzzi: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia
Lei Lu: Center for Motor Neuron Biology and Disease, Columbia University
Elisa Caffarelli: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia
Neil A. Shneider: Center for Motor Neuron Biology and Disease, Columbia University
Mariangela Morlando: Deparment of Biology and Biotechnology ‘Charles Darwin’, Sapienza University of Rome
Irene Bozzoni: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms14741

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