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

The RNA-binding protein FUS participates in several RNA biosynthetic processes and hasbeen linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporaldementia. Here we report that FUS controls back-splicing reactions leading to circular RNA(circRNA) production. We identified circRNAs expressed inin vitro-derived mouse motorneurons (MNs) and determined that the production of a considerable number of thesecircRNAs is regulated by FUS. Using RNAi and overexpression of wild-type and ALS-asso-ciated FUS mutants, we directly correlate the modulation of circRNA biogenesis withalteration of FUS nuclear levels and with putative toxic gain of function activities. We alsodemonstrate that FUS regulates circRNA biogenesis by binding the introns flanking theback-splicing junctions and that this control can be reproduced with artificial constructs. MostcircRNAs are conserved in humans and specific ones are deregulated in human-inducedpluripotent stem cell-derived MNs carrying the FUSP525Lmutation associated with ALS