title: FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis.
abstract: BACKGROUND
  FUS/TLS is an RNA-binding protein whose genetic mutations or pathological inclusions are associated with neurological diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and essential tremor (ET). It is unclear whether their pathogenesis is mediated by gain or loss of function of FUS/TLS.
  
  
  RESULTS
  Here, we established outbred FUS/TLS knockout mice to clarify the effects of FUS/TLS dysfunction in vivo. We obtained homozygous knockout mice that grew into adulthood. Importantly, they did not manifest ALS- or ET-like phenotypes until nearly two years. Instead, they showed distinct histological and behavioral alterations including vacuolation in hippocampus, hyperactivity, and reduction in anxiety-like behavior. Knockout mice showed transcriptome alterations including upregulation of Taf15 and Hnrnpa1, while they have normal morphology of RNA-related granules such as Gems.
  
  
  CONCLUSIONS
  Collectively, FUS/TLS depletion causes phenotypes possibly related to neuropsychiatric and neurodegenerative conditions, but distinct from ALS and ET, together with specific alterations in RNA metabolisms.
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. kino@my-pharm.ac.jp.|CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan. kino@my-pharm.ac.jp.|Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. kino@my-pharm.ac.jp.|Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan. kino@my-pharm.ac.jp.|Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan. kino@my-pharm.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
authors.affiliation: Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. c_washizu@brain.riken.jp.
authors.forename: Chika
authors.initials: C
authors.lastname: Washizu
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. kurosawa@brain.riken.jp.|CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan. kurosawa@brain.riken.jp.|Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. kurosawa@brain.riken.jp.|Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan. kurosawa@brain.riken.jp.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kurosawa
authors.affiliation: Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. y-mizuki@brain.riken.jp.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. miyazaki@brain.riken.jp.|CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan. miyazaki@brain.riken.jp.|Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. miyazaki@brain.riken.jp.|Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan. miyazaki@brain.riken.jp.
authors.forename: Haruko
authors.initials: H
authors.lastname: Miyazaki
authors.affiliation: Research Resource Center, Brain Science Institute, RIKEN, Saitama, Japan. atakumi@brain.riken.jp.
authors.forename: Takumi
authors.initials: T
authors.lastname: Akagi
authors.affiliation: Research Resource Center, Brain Science Institute, RIKEN, Saitama, Japan. tom@brain.riken.jp.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hashikawa
authors.affiliation: Department of Clinical Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Japan. doi@rkd.d-bs.com.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Doi
authors.affiliation: CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan. toru.takumi@riken.jp.|Laboratory for Mental Biology, Brain Science Institute, RIKEN, Saitama, Japan. toru.takumi@riken.jp.|Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. toru.takumi@riken.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
authors.affiliation: Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada. hicksgg@cc.umanitoba.ca.
authors.forename: Geoffrey G
authors.initials: GG
authors.lastname: Hicks
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. nhattori@juntendo.ac.jp.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan. tshimogori@brain.riken.jp.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Shimogori
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. nnukina@juntendo.ac.jp.|CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan. nnukina@juntendo.ac.jp.|Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. nnukina@juntendo.ac.jp.|Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan. nnukina@juntendo.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001007:Anxiety / Q000523:psychology*; D001522:Behavior, Animal; D004195:Disease Models, Animal; D020329:Essential Tremor / Q000235:genetics / Q000503:physiopathology; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics; D006720:Homozygote; D006948:Hyperkinesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D034702:RNA-Binding Protein FUS / Q000172:deficiency / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics; D015854:Up-Regulation
chemical_list: C000599551:FUS protein, mouse; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; D035381:TATA-Binding Protein Associated Factors