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Cell Rep. 2019 Mar 19;26(12):3313-3322.e5. doi: 10.1016/j.celrep.2019.02.086.

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

Author information

1
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
2
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Medical Scientist Training Program, Columbia University Medical Center, New York, NY 10032, USA.
3
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
4
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA.
5
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biochemistry & Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA; Sulzberger Columbia Genome Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: pas2182@cumc.columbia.edu.

Abstract

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.

KEYWORDS:

fragile X syndrome; ribosome profiling; translational regulation

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