title: Translocated in liposarcoma regulates the distribution and function of mammalian enabled, a modulator of actin dynamics.
abstract: Translocated in liposarcoma/fused in sarcoma (TLS/FUS) is an RNA-binding protein that regulates the splicing pattern of mRNA transcripts and is known to cause a type of familial amyotrophic lateral sclerosis (ALS). In the absence of TLS, Mammalian enabled (Mena), an actin-regulatory protein and a target of TLS, undergoes preferential alternative splicing. In the present study, we show that the ablation of TLS dysregulates the subcellular location and functions of Mena. When TLS knockout (KO) mouse embryonic fibroblasts (MEFs) were transfected with wild-type Mena, it no longer accumulated at focal adhesions and peripheral structures, whereas the localization of the alternatively spliced form was maintained. Additionally, the ability of Mena to suppress the motility of cells was lost in TLS KO MEFs. Moreover, Mena failed to promote neurite outgrowth in TLS KO primary neurons. Taken together, TLS is intimately involved in the local cytoskeletal dynamics surrounding Mena in both fibroblasts and neurons. The robust change in cytoskeletal dynamics, as indicated by the dysregulation of Mena in TLS KO cells, provides a new insight into the pathogenesis of certain types of ALS.
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Sugiura
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.|RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kurosaka
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.|RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakai
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.|RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Fukumoto
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maruyama
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imaizumi
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.|RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D003598:Cytoskeletal Proteins; C102176:Enah protein, mouse; D008840:Microfilament Proteins; D012333:RNA, Messenger; D034702:RNA-Binding Protein FUS
keywords: ALS; RNA-binding protein; actin; alternative splicing; cytoskeleton