Abstract
Fragile X syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of FMR1, which encodes the translational repressor fragile X mental retardation protein (FMRP). FMRP and cytoplasmic polyadenylation element–binding protein (CPEB), an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs and may mediate a translational homeostasis that, when imbalanced, results in FXS. Consistent with this possibility, Fmr1−/y; Cpeb1−/− double-knockout mice displayed amelioration of biochemical, morphological, electrophysiological and behavioral phenotypes associated with FXS. Acute depletion of CPEB1 in the hippocampus of adult Fmr1−/y mice rescued working memory deficits, demonstrating reversal of this FXS phenotype. Finally, we find that FMRP and CPEB1 balance translation at the level of polypeptide elongation. Our results suggest that disruption of translational homeostasis is causal for FXS and that the maintenance of this homeostasis by FMRP and CPEB1 is necessary for normal neurologic function.
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Acknowledgements
We thank N. Dawra for technical assistance, P. Lombroso (Yale University) and C. Proud (University of Southampton) for kind gifts of antibodies (STEP and eEF2, respectively), J. Pelletier (McGill University) for the kind gift of hippuristanol and members of the Richter lab for helpful discussions. T.U. and N.G.F. gratefully acknowledge fellowships from the FRAXA Research Foundation. J.A.H. was supported by US National Institutes of Health NRSA Postdoctoral Fellowship F32GM095060. This work was supported by NIH grants GM46779 and NS079415 to J.D.R. and MH086509 to S. Akbarian.
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T.U. and J.D.R. conceived of the initial project with much input from L.J.L. T.U., N.G.F. and M.J. designed and performed the majority of the experiments. H.K. and E.K. performed the electrophysiology experiments in Figure 1c,d and Supplementary Figure 4a,b. J.M.A. performed the electrophysiology experiments in Supplementary Figure 4c–e. S. Anilkumar and S.C. performed spine density analysis in Figure 1e,f and Supplementary Figure 5a,b. M.I. created and tested the CPEB antibody used in Supplementary Figure 2f. J.A.H. performed the bioinformatics analysis in Supplementary Table 1. V.C.N. and G.J.B. performed the immunocytochemistry analysis in Supplementary Figure 2a,b. T.U., N.G.F., M.J., K.N. and S. Akbarian contributed to the behavioral experiments in Figure 2. N.G.F. and J.D.R. wrote the manuscript. All authors contributed to interpretation and discussion of results and to editing of the manuscript.
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Udagawa, T., Farny, N., Jakovcevski, M. et al. Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat Med 19, 1473–1477 (2013). https://doi.org/10.1038/nm.3353
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DOI: https://doi.org/10.1038/nm.3353
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