Cell
Volume 146, Issue 2, 22 July 2011, Pages 247-261
Journal home page for Cell

Article
FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism

https://doi.org/10.1016/j.cell.2011.06.013Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► Identification of a robust, reproducible, novel set of in vivo FMRP targets ► FMRP targets encode key pre- and postsynaptic proteins and autism candidate genes ► FMRP stalls ribosomes along the coding region of its mRNA targets ► Acute and genetic loss of FMRP relieves stalling and increases protein synthesis

Cited by (0)

4

Present address: Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA

5

Present address: Case Western Reserve University, Center for RNA Molecular Biology, Wood Building, RT100, 10900 Euclid Avenue, Cleveland, OH 44106, USA