TY - JOUR
T1 - FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism
AU - Darnell, Jennifer C.
AU - Van Driesche, Sarah J.
AU - Zhang, Chaolin
AU - Hung, Ka Ying Sharon
AU - Mele, Aldo
AU - Fraser, Claire E.
AU - Stone, Elizabeth F.
AU - Chen, Cynthia
AU - Fak, John J.
AU - Chi, Sung Wook
AU - Licatalosi, Donny D.
AU - Richter, Joel D.
AU - Darnell, Robert B.
N1 - Funding Information:
We thank J. Pelletier for providing hippuristanol, E. Khandjian for anti-FXR1P antibody, N. Heintz for the transgenic mice expressing tagged ribosomal protein EGFP-rpL10a, and the members of the Darnell laboratory for advice and suggestions throughout the course of this work. We are grateful to E. Sphicas and K. Uryu for help with electron microscopy, and Xuning Wang and Scott Dewell for help with bioinformatics and high-throughput sequencing. This work was supported by the NIH (HD40647 to J.C.D., AG30323, GM46779, and HD37267 to J.D.R., GM95713 to C.Z., and NS34389 and NS40955 to R.B.D.), an NSF grant to S.J.V., MSTP-GM07749 to C.E.F., and the Rockefeller University Hospital CTSA Grant UL1 RR024143. R.B.D. is an Investigator of the Howard Hughes Medical Institute.
PY - 2011/7/22
Y1 - 2011/7/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79960779323&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2011.06.013
DO - 10.1016/j.cell.2011.06.013
M3 - Article
C2 - 21784246
AN - SCOPUS:79960779323
SN - 0092-8674
VL - 146
SP - 247
EP - 261
JO - Cell
JF - Cell
IS - 2
ER -