title: FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons.
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 FUSP525Lmutation associated with ALS.
authors.affiliation: 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.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Errichelli
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome 00161, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Dini Modigliani
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome 00161, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Laneve
authors.affiliation: Deparment of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Colantoni
authors.affiliation: Deparment of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Legnini
authors.affiliation: 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.
authors.forename: Davide
authors.initials: D
authors.lastname: Capauto
authors.affiliation: 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.
authors.forename: Alessandro
authors.identifier: 0000-0001-9999-7223
authors.initials: A
authors.lastname: Rosa
authors.affiliation: 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.
authors.forename: Riccardo
authors.initials: R
authors.lastname: De Santis
authors.affiliation: Deparment of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Scarfò
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome 00161, Italy.
authors.forename: Giovanna
authors.identifier: 0000-0002-6517-9107
authors.initials: G
authors.lastname: Peruzzi
authors.affiliation: Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, New York, New York 10032, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Lu
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome 00161, Italy.|Institute of Molecular Biology and Pathology, CNR, Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Caffarelli
authors.affiliation: Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, New York, New York 10032, USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Shneider
authors.affiliation: Deparment of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, P.le A. Moro 5, Rome 00185, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Morlando
authors.affiliation: 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.|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.
authors.forename: Irene
authors.initials: I
authors.lastname: Bozzoni
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007438:Introns / Q000235:genetics; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology*; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D000079962:RNA, Circular; D034702:RNA-Binding Protein FUS / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D013116:Spinal Cord / Q000166:cytology
chemical_list: C000599551:FUS protein, mouse; D000079962:RNA, Circular; D034702:RNA-Binding Protein FUS; D012313:RNA