FUS controls muscle differentiation through phase separation-mediated recruitment of the transcription factors MEF2 and ETV5
Abstract 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.
Authors
- Anne‐Laurence Boutillier (ORCID: https://orcid.org/0000-0002-2317-9280)
- Dagmar Zeuschner (ORCID: https://orcid.org/0000-0002-6712-0192)
- Albert C. Ludolph (ORCID: https://orcid.org/0000-0002-5401-0904)
- Maria Demestre (ORCID: https://orcid.org/0000-0002-3672-5703)
- Marica Catinozzi (ORCID: https://orcid.org/0000-0002-9211-9951)
- Saskia Hutten
- Luc Dupuis (ORCID: https://orcid.org/0000-0002-0902-5824)
- Hannah Walgrave (ORCID: https://orcid.org/0000-0003-3368-0690)
- Angela Rosenbohm (ORCID: https://orcid.org/0000-0001-9700-0338)
- Laura Tzeplaeff (ORCID: https://orcid.org/0009-0003-7643-3232)
- Gina Picchiarelli
- Pierre Cauchy (ORCID: https://orcid.org/0000-0002-0659-0799)
- Pierre Hener
- Annemarie Huebers
- Marije Been (ORCID: https://orcid.org/0000-0003-3856-4605)
- Stéphane Dieterle
- Tobias M. Boeckers (ORCID: https://orcid.org/0000-0002-1486-8535)
- Dorothee Dormann (ORCID: https://orcid.org/0000-0002-9260-2775)
- Clotilde Lagier‐Tourenne (ORCID: https://orcid.org/0000-0002-3058-8322)
- Salim Megat (ORCID: https://orcid.org/0000-0003-2186-6770)
- Anne Wienand (ORCID: https://orcid.org/0000-0001-6711-4713)
- Valérie Demais (ORCID: https://orcid.org/0000-0003-1328-1115)
- Erik Storkebaum (ORCID: https://orcid.org/0000-0002-9519-5642)
- Pascal Kessler (ORCID: https://orcid.org/0000-0003-3323-3647)
- Chantal Sellier (ORCID: https://orcid.org/0000-0003-2933-5464)
- Nibha Mishra
- Amr Aly
- Isabelle Weber
- Erin Sternburg
- Angela Bonanno (ORCID: https://orcid.org/0009-0008-1428-2017)
- Javier Lobo-Mancheno (ORCID: https://orcid.org/0009-0007-7155-515X)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2026-07-22
- DOI
- https://doi.org/10.1038/s44318-026-00874-1
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00