A heterogeneous set of FMR1 proteins is widely distributed in mouse tissues and is modulated in cell culture

Ew, Khandjian; Fortin, Anny; Thibodeau, Alain; Tremblay, Sarah; Côté, Francine; Devys, Didier; Jl, Mandel; Rousseau, François

doi:10.1093/hmg/4.5.783

Cited by 118 publications

(84 citation statements)

References 16 publications

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“…FMRP is widely, but not ubiquitously, expressed in human tissues, with particularly high levels of expression in the brain and testes . Patterns of expression for Fmr1 transcripts and FMRP isoforms have been found to be similar in most tissues amongst different species (Khandjian et al, 1995;Verheij et al, 1995). FMRP and the two paralogous proteins FXR1P and FXR2P are highly conserved in mammals.…”

Section: The Fragile X Mental Retardation Gene and Proteinmentioning

confidence: 95%

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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Section: The Fragile X Mental Retardation Gene and Proteinmentioning

confidence: 95%

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

et al. 2010

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“…FMRP is expressed at higher levels during development in mammals (Khandjian et al, 1995;Lu et al, 2004;Singh et al, 2007;Wang et al, 2004), but there is no indication of whether developmental regulation occurs at the level of transcription or translation. FMRP represses its own translation (Ashley, Jr et al, 1993;Brown et al, 1998;Ceman et al, 1999;Schaeffer et al, 2001;Sung et al, 2000), adding a complicating factor to understanding the mechanism of regulation.…”

Section: Dfmrp Expression and Function Is Developmentally Regulatedmentioning

confidence: 99%

Drosophilafragile X mental retardation protein developmentally regulates activity-dependent axon pruning

2008

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Fragile X Syndrome (FraX) is a broad-spectrum neurological disorder with symptoms ranging from hyperexcitability to mental retardation and autism. Loss of the fragile X mental retardation 1 (fmr1) gene product, the mRNA-binding translational regulator FMRP, causes structural over-elaboration of dendritic and axonal processes, as well as functional alterations in synaptic plasticity at maturity. It is unclear, however, whether FraX is primarily a disease of development, a disease of plasticity or both: a distinction that is vital for engineering intervention strategies. To address this crucial issue, we have used the Drosophila FraX model to investigate the developmental function of Drosophila FMRP (dFMRP). dFMRP expression and regulation of chickadee/profilin coincides with a transient window of late brain development. During this time, dFMRP is positively regulated by sensory input activity, and is required to limit axon growth and for efficient activity-dependent pruning of axon branches in the Mushroom Body learning/memory center. These results demonstrate that dFMRP has a primary role in activity-dependent neural circuit refinement during late brain development.

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“…Although FXR1P is found throughout the body, it is highly expressed in muscle and heart tissue where FMRP and FXR2P are mostly absent (Devys et al 1993;Coy et al 1995;Khandjian et al 1995). FXR1P has seven isoforms (Kirkpatrick et al 2001;Mientjes et al 2004), including one cardiac-specific isoform (Khandjian et al 1998) and three muscle-specific isoforms (Mientjes et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Fragile X protein family member FXR1P is regulated by microRNAs

Cheever

Blackwell

Ceman

2010

RNA

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FXR1P is one of two autosomal paralogs of the fragile X mental retardation protein FMRP. The absence of FMRP causes fragile X syndrome, the leading cause of hereditary mental retardation. FXR1P plays an important role in normal muscle development and has been implicated in facioscapulohumeral muscular dystrophy (FSHD). Its absence also causes cardiac abnormalities in both mice and zebrafish. To examine miRNA-mediated regulation of FMRP and FXR1P, we studied their expression in a conditional Dicer knockdown cell line, DT40. We found that FXR1P, but not FMRP, is significantly increased upon Dicer knockdown and the consequent reduction of miRNAs, suggesting that FXR1P is regulated by miRNAs while FMRP is not in DT40 cells. Expression of a luciferase reporter bearing the 39 untranslated region (39UTR) of FXR1 was significantly increased in the absence of miRNAs, confirming miRNA-mediated regulation of FXR1P, while a luciferase reporter bearing the FMR1 39UTR was not. We identified one of the regulatory regions in the 39UTR of FXR1 by removing a conserved, 8-nucleotide miRNA seed sequence common to miRNAs 25, 32, 92, 363, and 367 and demonstrated loss of miRNA-mediated suppression. Treatment with specific miRNA hairpin inhibitors to each of the miRNAs in the seed sequence showed that miRs 92b, 363, and 367 regulated FXR1P expression. Accordingly, overexpression of the miRNA 367 mimic significantly decreased endogenous FXR1P expression in human cell lines HEK-293T and HeLa. We report for the first time that FXR1P is regulated through miRNA binding, with one site being the miR-25/32/92/363/367 seed sequence.

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A heterogeneous set of FMR1 proteins is widely distributed in mouse tissues and is modulated in cell culture

Cited by 118 publications

References 16 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

Drosophilafragile X mental retardation protein developmentally regulates activity-dependent axon pruning

Fragile X protein family member FXR1P is regulated by microRNAs

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