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

By J. Darnell, Sarah J Van Driesche, Chaolin Zhang, K. Hung, Aldo Mele, C. Fraser, Elizabeth F Stone, Cynthia Chen, J. Fak, S. Chi and 3 more. Cell, 2011

2,041 citations recorded by the source corpus.

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 indicate that loss of a translational brake on the synthesis of a subset of synaptic proteins may contribute 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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/938ef69c910e44431f6c9295bcd1a3a11aa04807

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Citations in the corpus

Mutations causing syndromic autism define an axis of synaptic pathophysiology (2011, background): “Fragile X is caused by the loss of FMRP, an mRNA-binding protein that negatively regulates translatio”
Fragile X Mental Retardation Protein: A Paradigm for Translational Control by RNA-Binding Proteins (2015, background): “Darnell and co-workers used high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) to identify neuronal mRNA regulated by FMRP in the mouse brain (Darnell et al., 2011).”
Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018, neutral): “(33); mutationally constraint genes (104); syndromic and highly ranked”
Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity of Mammalian Proteomes (2011, background): “We also know that the rate of translation is not constant across a message, and translation pauses can regulate synthesis (Darnell et al., 2011; Morris and Geballe, 2000), folding (Kimchi-Sarfaty et al., 2007; Zhang et al., 2009), and localization of a protein (Mariappan et al., 2010) or mRNA…”
Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders (2014, background): “(5) Genes found to interact with fragile X mental retardation protein (FMRP).(34)”
A SPECTRAL APPROACH INTEGRATING FUNCTIONAL GENOMIC ANNOTATIONS FOR CODING AND NONCODING VARIANTS (2016, positive): “FMRP targets, as it has been shown that de novo ASD mutations are enriched among genes encoding FMRP targets [35, 36].”
FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export (2019, positive): “The best-studied function of FMRP is the negative regulation of mRNA translation; thus, fragile X syndrome may result in part from the aberrant expression of FMRP target genes (Darnell et al., 2011; Richter et al., 2015).”