FMRP links optimal codons to mRNA stability in neurons.

Proceedings of the National Academy of Sciences of the United States of America
Huan Raya ShuJoel D Richter

Abstract

Fragile X syndrome (FXS) is caused by inactivation of the FMR1 gene and loss of encoded FMRP, an RNA binding protein that represses translation of some of its target transcripts. Here we use ribosome profiling and RNA sequencing to investigate the dysregulation of translation in the mouse brain cortex. We find that most changes in ribosome occupancy on hundreds of mRNAs are largely driven by dysregulation in transcript abundance. Many down-regulated mRNAs, which are mostly responsible for neuronal and synaptic functions, are highly enriched for FMRP binding targets. RNA metabolic labeling demonstrates that, in FMRP-deficient cortical neurons, mRNA down-regulation is caused by elevated degradation and is correlated with codon optimality. Moreover, FMRP preferentially binds mRNAs with optimal codons, suggesting that it stabilizes such transcripts through direct interactions via the translational machinery. Finally, we show that the paradigm of genetic rescue of FXS-like phenotypes in FMRP-deficient mice by deletion of the Cpeb1 gene is mediated by restoration of steady-state RNA levels and consequent rebalancing of translational homeostasis. Our data establish an essential role of FMRP in codon optimality-dependent mRNA stability...Continue Reading

References

Aug 20, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Giovanni StefaniRobert B Darnell
Dec 21, 2007·Neuron·Gül DölenMark F Bear
Feb 12, 2008·Current Protocols in Molecular Biology·M A Collart, S Oliviero
Nov 6, 2008·Cell·Raymond J Kelleher, Mark F Bear
Jul 8, 2011·The Journal of Biological Chemistry·Jesse RinehartRichard P Lifton
Oct 25, 2011·Annual Review of Pathology·Michael R SantoroStephen T Warren
Nov 26, 2011·Algorithms for Molecular Biology : AMB·Ronny LorenzIvo L Hofacker
May 4, 2012·Nature·Carson C ThoreenDavid M Sabatini
Dec 25, 2012·Nature Structural & Molecular Biology·Sebastian Pechmann, Judith Frydman
Feb 26, 2013·Nature·Felice-Alessio BavaRaúl Méndez
Oct 22, 2013·Nature Medicine·Tsuyoshi UdagawaJoel D Richter
Aug 28, 2014·RNA·Benjamin NeymotinDavid Gresham
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
Mar 15, 2015·Cell·Vladimir PresnyakJeff Coller
Sep 10, 2015·Nature Reviews. Neuroscience·Joel D RichterEric Klann
Sep 15, 2015·Journal of Neurochemistry·Anna DolnikMichael J Schmeisser
Feb 18, 2016·Neural Plasticity·Joseph G DumanKimberley F Tolias
Mar 19, 2016·Molecular Cell·Yuichiro Mishima, Yukihide Tomari
Apr 5, 2016·Nature Communications·Zhengtao XiaoXuerui Yang
May 29, 2016·Proceedings of the National Academy of Sciences of the United States of America·Ricardos TabetHervé Moine
Nov 22, 2016·Nature Structural & Molecular Biology·Neelanjan MukherjeeUwe Ohler
Nov 24, 2016·BMC Genomics·Joshua G Dunn, Jonathan S Weissman
Feb 14, 2018·RNA·Andrew LugowskiOlivia S Rissland

❮ Previous
Next ❯

Citations

Feb 21, 2021·Nature Reviews. Neuroscience·Joel D Richter, Xinyu Zhao
May 6, 2021·Wiley Interdisciplinary Reviews. RNA·Christelle MorrisEmiliano P Ricci
Jun 1, 2021·Seminars in Cell & Developmental Biology·Jocelyn WidagdoVictor Anggono
Jul 27, 2021·Seminars in Cell & Developmental Biology·Mauricio M Oliveira, Eric Klann

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.