Title | FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Darnell JC, Van Driesche SJ, Zhang C, Hung KYing Sharo, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SWook, Licatalosi DD, Richter JD, Darnell RB |
Journal | Cell |
Volume | 146 |
Issue | 2 |
Pagination | 247-61 |
Date Published | 2011 Jul 22 |
ISSN | 1097-4172 |
Keywords | Animals, Autistic Disorder, Brain, Fragile X Mental Retardation Protein, Fragile X Syndrome, Humans, Mice, Mice, Knockout, Polyribosomes, Protein Biosynthesis, Ribosomes, RNA-Binding Proteins, Sequence Analysis, RNA, Synapses |
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. |
DOI | 10.1016/j.cell.2011.06.013 |
Alternate Journal | Cell |
PubMed ID | 21784246 |
PubMed Central ID | PMC3232425 |
Grant List | NS40955 / NS / NINDS NIH HHS / United States GM46779 / GM / NIGMS NIH HHS / United States HD40647 / HD / NICHD NIH HHS / United States K99 GM095713 / GM / NIGMS NIH HHS / United States HD37267 / HD / NICHD NIH HHS / United States / / Howard Hughes Medical Institute / United States GM95713 / GM / NIGMS NIH HHS / United States AG30323 / AG / NIA NIH HHS / United States NS34389 / NS / NINDS NIH HHS / United States UL1 RR024143 / RR / NCRR NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:10pm