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<p>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.</p>

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FUS controls muscle differentiation through phase separation-mediated recruitment of the transcription factors MEF2 and ETV5

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Gina Picchiarelli,
  • Anne Wienand,
  • Salim Megat,
  • Saskia Hutten,
  • Amr Aly,
  • Marije Been,
  • Isabelle Weber,
  • Angela Bonanno,
  • Nibha Mishra,
  • Erin Sternburg,
  • Pierre Cauchy,
  • Stéphane Dieterle,
  • Marica Catinozzi,
  • Javier Lobo-Mancheno,
  • Hannah Walgrave,
  • Valérie Demais,
  • Pierre Hener,
  • Pascal Kessler,
  • Laura Tzeplaeff,
  • Annemarie Huebers,
  • Dagmar Zeuschner,
  • Angela Rosenbohm,
  • Albert C Ludolph,
  • Anne-Laurence Boutillier,
  • Tobias Boeckers,
  • Dorothee Dormann,
  • Maria Demestre,
  • Chantal Sellier,
  • Clotilde Lagier-Tourenne,
  • Erik Storkebaum,
  • Luc Dupuis

摘要

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.