FMRP Phosphorylation Reveals an Immediate-Early Signaling Pathway Triggered by Group I mGluR and Mediated by PP2A

Narayanan, Usha; Nalavadi, Vijayalaxmi; Nakamoto, Mika; Pallas, David C.; Ceman, Stephanie; Bassell, Gary J.; Warren, Stephen T.

doi:10.1523/jneurosci.2969-07.2007

Cited by 205 publications

(259 citation statements)

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“…[46][47][48] The mechanism of how FMRP exerts its translation regulator function is still under investigation, however, previous findings have suggested that phosphorylation plays a role in the FMRP translation regulation function. 8,29,50 Aiming to understand if the FMRP phosphorylation results in any potential binding affinity difference to the G-quadruplex forming Shank1 RNA, we employed the previously created phosphorylated mimic form of FMRP isoform 1, FMRP S500D, in which serine 500 was mutated to aspartic acid. 29,50,51 The FMRP ISO1 and FMRP S500D were recombinantly expressed in E. coli cells.…”

Section: Resultsmentioning

confidence: 99%

“…6,7 FMRP normally represses the translation of its mRNA targets, the release of this repression being coupled with its dephosphorylation in response to an activation signal, which results in a burst of local protein synthesis. 8,9 In fragile X syndrome neurons, however, a subset of dendritic proteins synthesis is constitutively elevated due to the lack of FMRP even in the absence of an activation signal. 10 FMRP has been shown to use its RGG box domain to bind mRNA targets that form G-quadruplex structures.…”

Section: Introductionmentioning

confidence: 99%

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FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

et al. 2014

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Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, is caused by the loss of expression of the fragile X mental retardation protein (FMRP). FMRP, which regulates the transport and translation of specific mRNAs, uses its RGG box domain to bind mRNA targets that form G-quadruplex structures. One of the FMRP in vivo targets, Shank1 mRNA, encodes the master scaffold proteins of the postsynaptic density (PSD) which regulate the size and shape of dendritic spines because of their capacity to interact with many different PSD components. Due to their effect on spine morphology, altered translational regulation of Shank1 transcripts may contribute to the FXS pathology. We hypothesized that the FMRP interactions with Shank1 mRNA are mediated by the recognition of the G quadruplex structure, which has not been previously demonstrated. In this study we used biophysical techniques to analyze the Shank1 mRNA 3'-UTR and its interactions with FMRP and its phosphorylated mimic FMRP S500D. We found that the Shank1 mRNA 3 0 -UTR adopts two very stable intramolecular G-quadruplexes which are bound specifically and with high affinity by FMRP both in vitro and in vivo. These results suggest a role of G-quadruplex RNA motif as a structural element in the common mechanism of FMRP regulation of its dendritic mRNA targets.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

et al. 2014

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“…While the functional requirement for CKI-dependent dFMR1 phosphorylation is as of yet not understood, there is considerable evidence that the phosphorylation state of FMRP may actually determine its role in translation. Biochemical data demonstrate that most FMRP in granules is in the phosphorylated state while FMRP in the polysome fraction is dephosphorylated (Ceman et al 2003), suggesting a mechanism to switch state from an activator to a repressor, and an important regulatory role for kinases that phosphorylate FMRP (Narayanan et al 2007(Narayanan et al , 2008.…”

Section: Discussionmentioning

confidence: 99%

Genetic Modifiers ofdFMR1Encode RNA Granule Components in Drosophila

Cziko¹,

McCann

Howlett³

et al. 2009

Genetics

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Mechanisms of neuronal mRNA localization and translation are of considerable biological interest. Spatially regulated mRNA translation contributes to cell-fate decisions and axon guidance during development, as well as to long-term synaptic plasticity in adulthood. The Fragile-X Mental Retardation protein (FMRP/dFMR1) is one of the best-studied neuronal translational control molecules and here we describe the identification and early characterization of proteins likely to function in the dFMR1 pathway. Induction of the dFMR1 in sevenless-expressing cells of the Drosophila eye causes a disorganized (rough) eye through a mechanism that requires residues necessary for dFMR1/FMRP's translational repressor function. Several mutations in dco, orb2, pAbp, rm62, and smD3 genes dominantly suppress the sev-dfmr1 rough-eye phenotype, suggesting that they are required for dFMR1-mediated processes. The encoded proteins localize to dFMR1-containing neuronal mRNPs in neurites of cultured neurons, and/or have an effect on dendritic branching predicted for bona fide neuronal translational repressors. Genetic mosaic analyses indicate that dco, orb2, rm62, smD3, and dfmr1 are dispensable for translational repression of hid, a microRNA target gene, known to be repressed in wing discs by the bantam miRNA. Thus, the encoded proteins may function as miRNA-and/or mRNA-specific translational regulators in vivo.

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“…Multiple studies have shown that phosphorylation of FMRP at serine 499 in mouse (500 in human) results in translational repression [77][78][79][80][81]. Dephosphorylation of FMRP by PP2A in response to mGlu1/5 activation removes translational repression [82]. FMRP can also be ubiquitinated in response to mGlu1/5 activation [83], and this mechanism can occur locally within dendrites and at synapses [84].…”

Section: Mechanisms Of Fmrp-mediated Regulation Of Mrna Translation Imentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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FMRP Phosphorylation Reveals an Immediate-Early Signaling Pathway Triggered by Group I mGluR and Mediated by PP2A

Cited by 205 publications

References 43 publications

FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

Genetic Modifiers ofdFMR1Encode RNA Granule Components in Drosophila

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

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