The fragile x mental retardation protein binds and regulates a novel class of mRNAs containing u rich target sequences

Chen, L; Sw, Yun; Seto, Jeremy; W, Liu; Tóth, Miklós

doi:10.1016/s0306-4522(03)00406-8

Cited by 143 publications

(134 citation statements)

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“…Another class of transcripts that contain U-rich sequences have also been shown to be a target of FMRP (Chen et al, 2003;Dolzhanskaya et al, 2003).…”

Section: Sema3fmentioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

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“…Another class of transcripts that contain U-rich sequences have also been shown to be a target of FMRP (Chen et al, 2003;Dolzhanskaya et al, 2003).…”

Section: Sema3fmentioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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“…Furthermore, these experiments indicate that the RNA elements that direct Sema3A-induced translation are located in the 3'UTR. The 3'UTR of RhoA contains several elements implicated in translational regulation, including several binding sites for microRNAs 21 , and a binding site for FMRP, an RNA-binding protein that regulates translation 22 ( Supplementary Fig. 7).…”

mentioning

confidence: 99%

Local translation of RhoA regulates growth cone collapse

Hengst

Cox

et al. 2005

Nature

382

450

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Neuronal development requires highly coordinated regulation of the cytoskeleton within the developing axon. This dynamic regulation manifests itself in axonal branching, turning, and pathfinding, presynaptic differentiation, and growth cone collapse and extension. Semaphorin 3A (Sema3A), a secreted guidance cue that primarily acts to repel axons from inappropriate targets, induces cytoskeletal rearrangements that results in growth cone collapse 1 . These effects require intra-axonal mRNA translation. Here we show that transcripts for RhoA, a small GTPase that regulates the actin cytoskeleton, are localized to developing axons and growth cones, and this localization is mediated by an axonal targeting element located in the RhoA 3'UTR. Sema3A induces intra-axonal translation of RhoA mRNA and this local translation of RhoA is necessary and sufficient for Sema3A-mediated growth cone collapse. These studies indicate that local RhoA translation regulates the neuronal cytoskeleton and identify a novel mechanism for the regulation of RhoA signaling.Studies using Xenopus retinal axons demonstrated that cytoskeletal regulation of the growth cone by Sema3A requires intra-axonal, or "local", mRNA translation 2 . Sema3A treatment results in increased protein synthesis in growth cones as evidenced by metabolic labeling experiments and by phosphorylation of elongation factor 4E-BP1 2 . These effects occur within minutes of Sema3A application 2 . Furthermore, Sema3A-mediated growth cone collapse is blocked by ribosomal inhibitors. The mRNA translation that is required for Sema3A-mediated growth cone collapse occurs in the axon, as both Sema3A-induced collapse and inhibition of this collapse by ribosomal inhibitors is preserved in axons that are severed from their cell bodies 2 .To determine if intra-axonal mRNA translation is required for Sema3A signaling in mammalian neurons, we examined Sema3A-mediated growth cone collapse in embryonic rat dorsal root ganglia (DRG) explant cultures 3 -5 . To eliminate the possibility that the effects of Sema3A were mediated through somatic translation, axons were severed from their cell bodies 2 ( Supplementary Fig. 1a). Treatment of severed axons with Sema3A for 60 min resulted in an increase in collapsed growth cones from 17 ± 1.3% to 75 ± 2.8 % ( Supplementary Fig. 1b, c, g). This effect was blocked by pretreatment of axons with either cycloheximide or anisomycin ( Supplementary Fig. 1d-f), both of which are ribosomal inhibitors. Pretreatment of these cultures with rapamycin, an inhibitor of cap-dependent translation 6 , also blocked Sema3A-mediated growth cone collapse. Together, these data indicate that the requirement forCorrespondence and requests for materials should be addressed to S.R.J. (e-mail:srj2003@med.cornell.edu).. * These authors contributed equally to this work.Supplementary Information accompanies the paper on Nature's website (http://www.nature.com). Competing interests statementThe authors declare that they have no competing financial interests. Supplementary ...

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“…These results are helpful to explain why decreased MAP1B expression is more obviously in adult KO mice than in neonatal KO mice [20] . Besides the down-regulated MAP1B as demonstrated by Chen et al and us, some researches showed that other target-mRNAs and proteins were also decreased in absence of FMRP [8,18] . Taken together, these results imply that the interaction between FMRP, polyribosome and mRNAs is extremely complex.…”

Section: Discussionmentioning

confidence: 74%

“…This hypothesis has been supported by the later study which MAP1B mRNA was inappropriately over-translated in both Drosophila dFmr1 (dfxr) null [6] and mouse Fmr1 KO models [1,7] . Inversely, other report showed that MAP1B had a decrease tendency in the fron- tal lobe and hippocampus of adult fragile X mice and got statistical significance in the cerebellum [8] . In the present study, we found that MAP1B was significantly decreased in every brain subregion of adult KO mice and in the hippocampus and cerebellum of neonatal KO mice compared with the age-matched WT mice, which is in accordance with the report of Chen et al Hinds HL et al demonstrated that FMRP was high expressed in mouse brain during early embryogenesis period and gradually declined to a steadystate level during late embryogenesis period, and then it was high expressed again in adult [19] .…”

Section: Discussionmentioning

confidence: 93%

“…Furthermore, the aberrantly elevated MAP1B protein was found abnormally increase the microtubule stability in Fmr1-KO neurons [7] . However, another research showed that MAP1B decreased in the cerebellum of Fmr1-KO mice [8] . Therefore, how FMRP regulates MAP1B translation in fragile X neurons and governs normal synapse development in the brain remains elusive.…”

Section: Introductionmentioning

confidence: 95%

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Expression changes of microtubule associated protein 1B in the brain of Fmr1 knockout mice

Wei

Sun

et al. 2007

Neurosci. Bull.

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Objective To explore the regulatory effect of fragile X mental retardation protein (FMRP) on the translation of microtubule associated protein 1B (MAP1B). Methods The expressions of MAP1B protein and MAP1B mRNA in the brains of 1-week and 6-week old fragile X mental retardation-1 (Fmr1) knockout (KO) mice were investigated by immunohistochemistry, Western blot, and in situ hybridization, with the age-matched wild type mice (WT) as controls. Results The mean optical density (MOD) of MAP1B was significantly decreased in each brain region in KO6W compared with WT6W, whereas in KO1W, this decrease was only found in the hippocampus and cerebellum. MAP1B in 6-week mice was much less than that in 1-week mice of the same genotype. The results of Western blot and in situ hybridization showed that MAP1B protein and MAP1B mRNA were significantly decreased in the hippocampus of both KO1W and KO6W. Conclusion The decreased MAP1B protein and MAP1B mRNA in the Fmr1 knockout mice indicate that FMRP may positively regulate the expression of MAP1B.

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The fragile x mental retardation protein binds and regulates a novel class of mRNAs containing u rich target sequences

Cited by 143 publications

References 38 publications

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

Local translation of RhoA regulates growth cone collapse

Expression changes of microtubule associated protein 1B in the brain of Fmr1 knockout mice

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