Widespread Alterations in Translation Elongation in the Brain of Juvenile Fmr1 Knockout Mice

• Main Authors: Sohani Das Sharma, Jordan B. Metz, Hongyu Li, Benjamin D. Hobson, Nicholas Hornstein, David Sulzer, Guomei Tang, Peter A. Sims
• Format: Article
• Language: English
• Published: Elsevier 2019-03-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719302724

Summary: FMRP (fragile X mental retardation protein) is a polysome-associated RNA-binding protein encoded by Fmr1 that is lost in fragile X syndrome. Increasing evidence suggests that FMRP regulates both translation initiation and elongation, but the gene specificity of these effects is unclear. To elucidate the impact of Fmr1 loss on translation, we utilize ribosome profiling for genome-wide measurements of ribosomal occupancy and positioning in the cortex of 24-day-old Fmr1 knockout mice. We find a remarkably coherent reduction in ribosome footprint abundance per mRNA for previously identified, high-affinity mRNA binding partners of FMRP and an increase for terminal oligopyrimidine (TOP) motif-containing genes canonically controlled by mammalian target of rapamycin-eIF4E-binding protein-eIF4E binding protein-eukaryotic initiation factor 4E (mTOR-4E-BP-eIF4E) signaling. Amino acid motif- and gene-level analyses both show a widespread reduction of translational pausing in Fmr1 knockout mice. Our findings are consistent with a model of FMRP-mediated regulation of both translation initiation through eIF4E and elongation that is disrupted in fragile X syndrome. : Silencing of Fmr1, the gene that encodes FMRP, causes fragile X syndrome. Das Sharma et al. used ribosome profiling in the cortex of 24-day-old Fmr1 knockout mice to dissect FMRP-mediated translational regulation. Fmr1 loss leads to a relief of translational pausing across a large number of genes. Keywords: fragile X syndrome, translational regulation, ribosome profiling