FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism

Jennifer C. Darnell, Sarah J. Van Driesche, Chaolin Zhang, Ka Ying Sharon Hung, Aldo Mele, Claire E. Fraser, Elizabeth F. Stone, Cynthia Chen, John J. Fak, Sung Wook Chi, Donny D. Licatalosi, Joel D. Richter, Robert B. Darnell

Research output: Contribution to journalArticle

1086 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)247-261
Number of pages15
JournalCell
Volume146
Issue number2
DOIs
Publication statusPublished - 2011 Jul 22

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Darnell, J. C., Van Driesche, S. J., Zhang, C., Hung, K. Y. S., Mele, A., Fraser, C. E., Stone, E. F., Chen, C., Fak, J. J., Chi, S. W., Licatalosi, D. D., Richter, J. D., & Darnell, R. B. (2011). FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell, 146(2), 247-261. https://doi.org/10.1016/j.cell.2011.06.013