scholarly journals First in vivo evidence of microRNA-induced fragile X mental retardation syndrome

2006 ◽  
Vol 11 (7) ◽  
pp. 616-617 ◽  
Author(s):  
S-L Lin ◽  
S-Je Chang ◽  
S-Y Ying
Keyword(s):  
Mental Retardation ◽  
Fragile X ◽  
Fragile X Mental Retardation

scholarly journals DrosophilaTorsin Protein Regulates Motor Control and Stress Sensitivity and Forms a Complex with Fragile-X Mental Retardation Protein

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Phuong Nguyen ◽  
Jong Bok Seo ◽  
Hyo-Min Ahn ◽  
Young Ho Koh
Keyword(s):  
Mental Retardation ◽  
Protein Complexes ◽  
Fragile X ◽  
Stress Sensitivity ◽  
Altered Expression ◽  
Fragile X Mental Retardation ◽  
Evolutionarily Conserved ◽  
Mental Retardation Protein ◽  
Synaptic Boutons

We investigated unknownin vivofunctions of Torsin by usingDrosophilaas a model. Downregulation ofDrosophilaTorsin (DTor) by DTor-specific inhibitory double-stranded RNA (RNAi) induced abnormal locomotor behavior and increased susceptibility to H2O2. In addition, altered expression of DTor significantly increased the numbers of synaptic boutons. One important biochemical consequence of DTor-RNAi expression in fly brains was upregulation of alcohol dehydrogenase (ADH). Altered expression of ADH has also been reported inDrosophilaFragile-X mental retardation protein (DFMRP) mutant flies. Interestingly, expression of DFMRP was altered in DTor mutant flies, and DTor and DFMRP were present in the same protein complexes. In addition, DTor and DFMRP immunoreactivities were partially colocalized in several cellular organelles in larval muscles. Furthermore, there were no significant differences between synaptic morphologies ofdfmrpnull mutants anddfmrpmutants expressing DTor-RNAi. Taken together, our evidences suggested that DTor and DFMRP might be present in the same signaling pathway regulating synaptic plasticity. In addition, we also found that human Torsin1A and human FMRP were present in the same protein complexes, suggesting that this phenomenon is evolutionarily conserved.

scholarly journals Oligomerization properties of fragile-X mental-retardation protein (FMRP) and the fragile-X-related proteins FXR1P and FXR2P

1999 ◽  
Vol 343 (3) ◽  
pp. 517-523 ◽  
Author(s):  
Filippo TAMANINI ◽  
Leontine VAN UNEN ◽  
Cathy BAKKER ◽  
Nicoletta SACCHI ◽  
Hans GALJAARD ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Mammalian Cells ◽  
Fragile X ◽  
Gel Filtration ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Heterotypic Interactions ◽  
Molecular Masses ◽  
Related Proteins

The absence of fragile-X mental-retardation protein (FMRP) results in fragile-X syndrome. Two other fragile-X-related (FXR) proteins have been described, FXR1P and FXR2P, which are both very similar in amino acid sequence to FMRP. Interaction between the three proteins as well as with themselves has been demonstrated. The FXR proteins are believed to play a role in RNA metabolism. To characterize a possible functional role of the interacting proteins the complex formation of the FXR proteins was studied in mammalian cells. Double immunofluorescence analysis in COS cells over-expressing either FMRP ISO12/FXR1P or FMRP ISO12/FXR2P confirmed heterotypic interactions. However, Western-blotting studies on cellular homogenates containing physiological amounts of the three proteins gave different indications. Gel-filtration experiments under physiological as well as EDTA conditions showed that the FXR proteins were in complexes of > 600 kDa, as parts of messenger ribonuclear protein (mRNP) particles associated with polyribosomes. Salt treatment shifted FMRP, FXR1P and FXR2P into distinct intermediate complexes, with molecular masses between 200 and 300 kDa. Immunoprecipitations of FMRP as well as FXR1P from the dissociated complexes revealed that the vast majority of the FXR proteins do not form heteromeric complexes. Further analysis by [35S]methionine labelling in vivo followed by immunoprecipitation indicated that no proteins other than the FXR proteins were present in these complexes. These results suggest that the FXR proteins form homo-multimers preferentially under physiological conditions in mammalian cells, and might participate in mRNP particles with separate functions.

scholarly journals Temporal-specific roles of fragile X mental retardation protein in the development of the hindbrain auditory circuit

Development ◽  
2020 ◽  
Vol 147 (21) ◽  
pp. dev188797
Author(s):  
Xiaoyu Wang ◽  
Ayelet Kohl ◽  
Xiaoyan Yu ◽  
Diego A. R. Zorio ◽  
Avihu Klar ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Rna Binding ◽  
Fragile X ◽  
Neuronal Cell ◽  
High Specificity ◽  
Fragile X Mental Retardation ◽  
Midline Crossing ◽  
Mental Retardation Protein ◽  
Axonal Targeting

ABSTRACTFragile X mental retardation protein (FMRP) is an RNA-binding protein abundant in the nervous system. Functional loss of FMRP leads to sensory dysfunction and severe intellectual disabilities. In the auditory system, FMRP deficiency alters neuronal function and synaptic connectivity and results in perturbed processing of sound information. Nevertheless, roles of FMRP in embryonic development of the auditory hindbrain have not been identified. Here, we developed high-specificity approaches to genetically track and manipulate throughout development of the Atoh1+ neuronal cell type, which is highly conserved in vertebrates, in the cochlear nucleus of chicken embryos. We identified distinct FMRP-containing granules in the growing axons of Atoh1+ neurons and post-migrating NM cells. FMRP downregulation induced by CRISPR/Cas9 and shRNA techniques resulted in perturbed axonal pathfinding, delay in midline crossing, excess branching of neurites, and axonal targeting errors during the period of circuit development. Together, these results provide the first in vivo identification of FMRP localization and actions in developing axons of auditory neurons, and demonstrate the importance of investigating early embryonic alterations toward understanding the pathogenesis of neurodevelopmental disorders.

scholarly journals The roles of Sp1, Sp3, USF1/USF2 and NRF-1 in the regulation and three-dimensional structure of the Fragile X mental retardation gene promoter

2005 ◽  
Vol 386 (2) ◽  
pp. 297-303 ◽  
Author(s):  
Daman KUMARI ◽  
Andrei GABRIELIAN ◽  
David WHEELER ◽  
Karen USDIN
Keyword(s):  
Mental Retardation ◽  
Transcription Initiation ◽  
Promoter Activity ◽  
Fragile X ◽  
Three Dimensional ◽  
Point Mutations ◽  
Gene Promoter ◽  
Dimensional Structure ◽  
Fragile X Mental Retardation

Expansion of a CGG·CCG-repeat tract in the 5′-untranslated region of the FMR1 (Fragile X mental retardation 1) gene causes its aberrant transcription. This produces symptoms ranging from premature ovarian failure and Fragile X associated tremor and ataxia syndrome to FMR syndrome, depending on the size of the expansion. The promoter from normal alleles shows four protein-binding regions in vivo. We had previously shown that in mouse brain extracts two of these sites are bound by USF1/USF2 (upstream stimulatory factors 1 and 2) heterodimers and NRF-1 (nuclear respiratory factor-1). We also showed that these sites are involved in the positive regulation of FMR1 transcription in neuronally derived cells. In the present study, we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity. We also show that, like Sp1 and E-box-binding proteins such as USF1 and USF2, NRF-1 causes DNA bending, in this case producing a bend of 57° towards the major groove. The combined effect of the four protein-induced bends on promoter geometry is the formation of a highly compact arch-like structure in which the 5′ end of the promoter is brought in close proximity to the 3′ end. We had previously shown that while point mutations in the GC-boxes decrease promoter activity, deletion of either one of them leads to an increase in promoter activity. We can reconcile these observations with the positive effect of Sp1 and Sp3 if protein-induced bending acts, at least in part, to bring together distally spaced factors important for transcription initiation.

scholarly journals Dicer-Derived MicroRNAs Are Utilized by the Fragile X Mental Retardation Protein for Assembly on Target RNAs

2006 ◽  
Vol 2006 ◽  
pp. 1-12 ◽  
Author(s):  
Isabelle Plante ◽  
Laetitia Davidovic ◽  
Dominique L. Ouellet ◽  
Lise-Andrée Gobeil ◽  
Sandra Tremblay ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Translational Control ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Fragile X ◽  
Rna Sequences ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Rnp Complex

In mammalian cells, fragile X mental retardation protein (FMRP) has been reported to be part of a microRNA (miRNA)-containing effector ribonucleoprotien (RNP) complex believed to mediate translational control of specific mRNAs. Here, using recombinant proteins, we demonstrate that human FMRP can act as a miRNA acceptor protein for the ribonuclease Dicer and facilitate the assembly of miRNAs on specific target RNA sequences. The miRNA assembler property of FMRP was abrogated upon deletion of its single-stranded (ss) RNA binding K-homology domains. The requirement of FMRP for efficient RNA interference (RNAi) in vivo was unveiled by reporter gene silencing assays using various small RNA inducers, which also supports its involvement in an ss small interfering RNA (siRNA)-containing RNP (siRNP) effector complex in mammalian cells. Our results define a possible role for FMRP in RNA silencing and may provide further insight into the molecular defects in patients with the fragile X syndrome.

scholarly journals In vivo neuronal function of the fragile X mental retardation protein is regulated by phosphorylation

2011 ◽  
Vol 21 (4) ◽  
pp. 900-915 ◽  
Author(s):  
R. L. Coffee ◽  
A. J. Williamson ◽  
C. M. Adkins ◽  
M. C. Gray ◽  
T. L. Page ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X ◽  
Neuronal Function ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein

scholarly journals In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Mody ◽  
Yoann Petibon ◽  
Paul Han ◽  
Darshini Kuruppu ◽  
Chao Ma ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Receptor Expression ◽  
Healthy Controls ◽  
Significant Group ◽  
Fragile X Mental Retardation ◽  
Potential Biomarker ◽  
The Brain

AbstractFragile X Syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the Fragile X Mental Retardation (FMR1) gene. The resulting loss of Fragile X Mental Retardation Protein (FMRP) leads to excessive glutamate signaling via metabotropic glutamate subtype 5 receptors (mGluR5) which has been implicated in the pathogenesis of the disorder. In the present study we used the radioligand 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB) in simultaneous PET-MR imaging of males with FXS and age- and gender-matched controls to assess the availability of mGlu5 receptors in relevant brain areas. Patients with FXS showed lower [18F]FPEB binding potential (p <  0.01), reflecting reduced mGluR5 availability, than the healthy controls throughout the brain, with significant group differences in insula, anterior cingulate, parahippocampal, inferior temporal and olfactory cortices, regions associated with deficits in inhibition, memory, and visuospatial processes characteristic of the disorder. The results are among the first to provide in vivo evidence of decreased availability of mGluR5 in the brain in individuals with FXS than in healthy controls. The consistent results across the subjects, despite the tremendous challenges with neuroimaging this population, highlight the robustness of the protocol and support for its use in drug occupancy studies; extending our radiotracer development and application efforts from mice to humans.

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