FUS controls muscle differentiation through phase separation-mediated recruitment of the transcription factors MEF2...

FUS is an RNA-binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show in this work that a heterozygous knock-in mutation in the mouse Fus gene leads to cell-autonomous ultrastructural defects in skeletal muscle, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionarily conserved cell-autonomous function of FUS in muscle development. Mechanistically, FUS is required for the transcription of MEF2 target genes, binds to the promoter of genes bound by ETS transcription factors, in particular ETV5, and co-activates the transcription of MEF2-dependent genes with ETV5. FUS phase-separates with ETV5 and MEF2A, and stimulation of MEF2-dependent transcription by FUS is dependent upon its phase separation properties. Finally, Etv5 haploinsufficiency exacerbates muscle weakness and atrophy in Fus knock-in mice. Our findings establish a key role for FUS in skeletal muscle differentiation through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.