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.
Related
- Human organ chip models recapitulate FRC-driven high endothelial venule differentiation, immune recruitment, and cancer-induced disruption
- Histone lactylation in fibroblast-like synoviocytes drives CXCL1-mediated immune cell recruitment in rheumatoid arthritis
- A phosphorylation-gated GAPDH-MAPK6-LBD1 module controls drought-responsive transcription
- A Regulatory Network of Transcription and Hormones Controls PCD and Autophagy in Grape Seed Abortion
- The transcription factor BCL11A restores differentiation potential to aged oligodendrocyte progenitor cells.
BibTeX
@article{picchiarelli2026controls,
title = {{FUS controls muscle differentiation through phase separation-mediated recruitment of the transcription factors MEF2 and ETV5}},
author = {Gina Picchiarelli and Anne Wienand and Salim Megat and Saskia Hutten and Amr Aly and Marije Been and Isabelle Weber and Angela Bonanno and Nibha Mishra and Erin Sternburg and Pierre Cauchy and Stéphane Dieterle and Marica Catinozzi and Javier Lobo-Mancheno and Hannah Walgrave and Valérie Demais and Pierre Hener and Pascal Kessler and Laura Tzeplaeff and Annemarie Huebers and Dagmar Zeuschner and Angela Rosenbohm and Albert C Ludolph and Anne-Laurence Boutillier and Tobias Boeckers and Dorothee Dormann and Maria Demestre and Chantal Sellier and Clotilde Lagier-Tourenne and Erik Storkebaum and Luc Dupuis},
journal = {The EMBO Journal},
year = {2026},
month = jul,
doi = {10.1038/s44318-026-00874-1},
url = {https://univoak.hal.science/hal-05758468v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - FUS controls muscle differentiation through phase separation-mediated recruitment of the transcription factors MEF2 and ETV5
AU - Gina Picchiarelli
AU - Anne Wienand
AU - Salim Megat
AU - Saskia Hutten
AU - Amr Aly
AU - Marije Been
AU - Isabelle Weber
AU - Angela Bonanno
AU - Nibha Mishra
AU - Erin Sternburg
AU - Pierre Cauchy
AU - Stéphane Dieterle
AU - Marica Catinozzi
AU - Javier Lobo-Mancheno
AU - Hannah Walgrave
AU - Valérie Demais
AU - Pierre Hener
AU - Pascal Kessler
AU - Laura Tzeplaeff
AU - Annemarie Huebers
AU - Dagmar Zeuschner
AU - Angela Rosenbohm
AU - Albert C Ludolph
AU - Anne-Laurence Boutillier
AU - Tobias Boeckers
AU - Dorothee Dormann
AU - Maria Demestre
AU - Chantal Sellier
AU - Clotilde Lagier-Tourenne
AU - Erik Storkebaum
AU - Luc Dupuis
PY - 2026
DA - 2026/07/22
JO - The EMBO Journal
DO - 10.1038/s44318-026-00874-1
UR - https://univoak.hal.science/hal-05758468v1
AB - 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.
SN - 0261-4189
SN - 1460-2075
ER -