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bioRxiv · 10.1101/319368

Widespread Alterations in Translation Elongation in the Brain of Juvenile Fmr1 Knock-Out Mice

Das Sharma, S.·Metz, J. B.·Li, H.·Hobson, B. D.·Hornstein, N.·Sulzer, D.·Tang, G.·Sims, P. A.
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Abstract

FMRP 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 used ribosome profiling for genome-wide measurements of ribosomal occupancy and positioning in the cortex of 24 day-old Fmr1 knock-out mice. We found 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 oligo-pyrimidine (TOP) motif-containing genes canonically controlled by mTOR-4EBP-eIF4E signaling. Amino acid motif- and gene-level analyses both showed a widespread reduction of translational pausing in Fmr1 knock-out 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.

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Das Sharma, S., Metz, J. B., Li, H., Hobson, B. D., Hornstein, N., Sulzer, D., Tang, G., Sims, P. A.. 2018-05-10. Widespread Alterations in Translation Elongation in the Brain of Juvenile Fmr1 Knock-Out Mice. https://doi.org/10.1101/319368

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