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

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). pp. 247-261. ISSN 00928674 (ISSN)

URL: http://www.scopus.com/inward/record.url?eid=2-s2.0...
DOI: 10.1016/j.cell.2011.06.013

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. © 2011 Elsevier Inc.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > FMRP
diseases & disorders > mental disorders > personality disorders > autism
diseases & disorders > congenital hereditary genetic diseases > fragile X syndrome
organism description > animal > mammal > rodent > mouse
CSHL Authors:
Depositing User: CSHL Librarian
Date Deposited: 09 Nov 2011 15:38
Last Modified: 29 Nov 2011 20:04
URI: http://repository.cshl.edu/id/eprint/15625

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