title: FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.
abstract: FMRP loss of function causes Fragile X syndrome (FXS) and autistic features. FMRP is a polyribosome-associated neuronal RNA-binding protein, suggesting that it plays a key role in regulating neuronal translation, but there has been little consensus regarding either its RNA targets or mechanism of action. Here, we use high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) to identify FMRP interactions with mouse brain polyribosomal mRNAs. FMRP interacts with the coding region of transcripts encoding pre- and postsynaptic proteins and transcripts implicated in autism spectrum disorders (ASD). We developed a brain polyribosome-programmed translation system, revealing that FMRP reversibly stalls ribosomes specifically on its target mRNAs. Our results suggest that loss of a translational brake on the synthesis of a subset of synaptic proteins contributes to FXS. In addition, they provide insight into the molecular basis of the cognitive and allied defects in FXS and ASD and suggest multiple targets for clinical intervention.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, NY 10065, USA. darneje@rockefeller.edu
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Darnell
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Van Driesche
authors.forename: Chaolin
authors.initials: C
authors.lastname: Zhang
authors.forename: Ka Ying Sharon
authors.initials: KY
authors.lastname: Hung
authors.forename: Aldo
authors.initials: A
authors.lastname: Mele
authors.forename: Claire E
authors.initials: CE
authors.lastname: Fraser
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Stone
authors.forename: Cynthia
authors.initials: C
authors.lastname: Chen
authors.forename: John J
authors.initials: JJ
authors.lastname: Fak
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Chi
authors.forename: Donny D
authors.initials: DD
authors.lastname: Licatalosi
authors.forename: Joel D
authors.initials: JD
authors.lastname: Richter
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins; D012270:Ribosomes / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D013569:Synapses / Q000378:metabolism*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D016601:RNA-Binding Proteins; C497684:Fmr1 protein, mouse