Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome

Sellier, Chantal; Freyermuth, Fernande; Tabet, Ricardos; Tran, Tuan Anh; He, Fang; Ruffenach, Frank; Alunni, Violaine; Moine, Hervé; Thibault, Christelle; Page, Adeline; Tassone, Flora; Willemsen, Rob; Disney, Matthew D.; Hagerman, Paul J.; Todd, Peter K.; Charlet‐Berguerand, Nicolas

doi:10.1016/j.celrep.2013.02.004

Cited by 223 publications

(256 citation statements)

References 50 publications

(82 reference statements)

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“…Lin28A/B enhances the growth of breast and colon tumors via inhibition of let-7 miRNA biogenesis (25). Fragile X-associated tremor/ataxia syndrome, a neurodegenerative disorder, is caused by the expansion of 55 to 200 CGG repeats in the 5= untranslated region of FMR1 that inhibits Drosha-mediated pri-miRNA processing through binding of the Drosha-DGCR8 complex to CGG repeats (53). Cardiac dysfunction in type I myotonic dystrophy is implicated in the reduction of miR-1 processing caused by the fall in the activity of MBNL1 as a positive regulator of processing from premiR-1 to miR-1 (54).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of NF90-NF45 Represses Myogenic MicroRNA Biogenesis, Resulting in Development of Skeletal Muscle Atrophy and Centronuclear Muscle Fibers

Taniguchi¹,

Higuchi²,

Yagyu³

et al. 2015

Molecular and Cellular Biology

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d MicroRNAs (miRNAs) are involved in the progression and suppression of various diseases through translational inhibition of target mRNAs. Therefore, the alteration of miRNA biogenesis induces several diseases. The nuclear factor 90 (NF90)-NF45 complex is known as a negative regulator in miRNA biogenesis. Here, we showed that NF90-NF45 double-transgenic (dbTg) mice develop skeletal muscle atrophy and centronuclear muscle fibers in adulthood. Subsequently, we found that the levels of myogenic miRNAs, including miRNA 133a (miR-133a), which promote muscle maturation, were significantly decreased in the skeletal muscle of NF90-NF45 dbTg mice compared with those in wild-type mice. However, levels of primary transcripts of the miRNAs (pri-miRNAs) were clearly elevated in NF90-NF45 dbTg mice. This result indicated that the NF90-NF45 complex suppressed miRNA production through inhibition of pri-miRNA processing. This finding was supported by the fact that processing of pri-miRNA 133a-1 (primiR-133a-1) was inhibited via binding of NF90-NF45 to the pri-miRNA. Finally, the level of dynamin 2, a causative gene of centronuclear myopathy and concomitantly a target of miR-133a, was elevated in the skeletal muscle of NF90-NF45 dbTg mice. Taken together, we conclude that the NF90-NF45 complex induces centronuclear myopathy through increased dynamin 2 expression by an NF90-NF45-induced reduction of miR-133a expression in vivo.M icroRNAs (miRNAs) are functional small noncoding RNAs 21 to 23 nucleotides in length. miRNAs bind to 3= untranslated regions (UTRs) of target mRNAs, leading to either mRNA degradation or translational inhibition. The functions of miRNAs influence biological phenomena and diseases such as development (1, 2), cell proliferation (3), differentiation (4), apoptosis (5), as well as tumorigenesis (6, 7).The biogenesis of miRNAs involves several steps (8). First, miRNA genes are transcribed as primary miRNAs (pri-miRNAs) by RNA polymerase II (9). Subsequently, these pri-miRNAs are processed into precursor miRNAs (pre-miRNAs) by a microprocessor complex composed of Drosha and DGCR8 (10-14). Thereafter, the pre-miRNAs are transported from the nucleus to the cytoplasm (15-17) and processed into mature miRNA duplexes by the Dicer complex (18)(19)(20). The functional strand of the duplex (mature miRNA) is loaded into the RNA-induced silencing complex (RISC) (21-23). As part of the RISC, miRNA binds to target mRNAs and induces their translational inhibition or degradation (20,(22)(23)(24). Recently, it was reported that some RNA-binding proteins negatively regulate miRNA biogenesis. For example, Lin28A/B (25), the Musashi homolog 2/Hu antigen R complex (26), and the nuclear factor 90 (NF90; also referred to as interleukin enhancer binding factor 3 [ILF3], NFAR1, or DRBP76)-nuclear factor 45 (NF45) complex (27) suppress miRNA processing through binding to pri-or pre-miRNAs.NF90 contains a functional nuclear localization signal, two double-stranded RNA (dsRNA)-binding motifs, a zinc finger nucleic acid-binding domain, an...

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Section: Discussionmentioning

confidence: 99%

Overexpression of NF90-NF45 Represses Myogenic MicroRNA Biogenesis, Resulting in Development of Skeletal Muscle Atrophy and Centronuclear Muscle Fibers

Taniguchi¹,

Higuchi²,

Yagyu³

et al. 2015

Molecular and Cellular Biology

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“…FXTAS and FXPOI are seen in the carriers of FMR1 premutation (PM) alleles that have 55-200 CGG-repeats. The clinical symptoms of those with FXTAS and FXPOI are thought to arise primarily from some deleterious consequence of the expression of the PM allele [26][27][28][29]. However, PM carriers often have symptoms that are reminiscent of those seen in FXS.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Screening to Identify Compounds That Increase Fragile X Mental Retardation Protein Expression in Neural Stem Cells Differentiated From Fragile X Syndrome Patient-Derived Induced Pluripotent Stem Cells

Kumari

Swaroop

Southall

et al. 2015

Stem Cells Translational Medicine

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a Key Words. Fragile X syndrome x Fragile X mental retardation protein assay x High-throughput screening x Fibroblasts x Induced pluripotent stem cells x Neural stem cells ABSTRACTFragile X syndrome (FXS), the most common form of inherited cognitive disability, is caused by a deficiency of the fragile X mental retardation protein (FMRP). In most patients, the absence of FMRP is due to an aberrant transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. FXS has no cure, and the available treatments only provide symptomatic relief. Given that FMR1 gene silencing in FXS patient cells can be partially reversed by treatment with compounds that target repressive epigenetic marks, restoring FMRP expression could be one approach for the treatment of FXS. We describe a homogeneous and highly sensitive time-resolved fluorescence resonance energy transfer assay for FMRP detection in a 1,536-well plate format. Using neural stem cells differentiated from an FXS patient-derived induced pluripotent stem cell (iPSC) line that does not express any FMRP, we screened a collection of approximately 5,000 known tool compounds and approved drugs using this FMRP assay and identified 6 compounds that modestly increase FMR1 gene expression in FXS patient cells. Although none of these compounds resulted in clinically relevant levels of FMR1 mRNA, our data provide proof of principle that this assay combined with FXS patient-derived neural stem cells can be used in a high-throughput format to identify better lead compounds for FXS drug development. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:800-808 SIGNIFICANCEIn this study, a specific and sensitive fluorescence resonance energy transfer-based assay for fragile X mental retardation protein detection was developed and optimized for high-throughput screening (HTS) of compound libraries using fragile X syndrome (FXS) patient-derived neural stem cells. The data suggest that this HTS format will be useful for the identification of better lead compounds for developing new therapeutics for FXS. This assay can also be adapted for FMRP detection in clinical and research settings.

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“…It has been suggested that the death of granulosa cells and perhaps oocytes themselves in POI and POF can recognize, as a pathogenic mechanism, a dynamic intracellular accumulation of cytotoxic amounts of aggregated CGG repeats that in turn sequester proteins like DROSHA and Sam68 [83]. The final result will be the interference with some important cellular functions.…”

Section: Fmr1 Gene Mutations and Reproductive Agingmentioning

confidence: 99%

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

Noto

Harrity

Walsh

et al. 2016

J Assist Reprod Genet

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Purpose This is a comprehensive review of the literature in this field attempting to put the FMR1 gene and its evaluation into context, both in general and for the reproductive health audience. Methods Online database search of publications with systematic review of all papers relevant to ovarian reserve and assisted reproduction was done. Results Relevant papers were identified and assessed, and an attempt was made to understand, rationalize and explain the divergent views in this field of study. Seminal and original illustrations were employed. Conclusions FMR1 is a highly conserved gene whose interpretation and effect on outcomes remains controversial in the reproductive health setting. Recent re-evaluations of the commonly accepted normal range have yielded interesting tools for possibly explaining unexpected outcomes in assisted reproduction. Fragile X investigations should perhaps become more routinely assessed in the reproductive health setting, particularly following a failed treatment cycle where oocyte quality is thought to be a contributing factor, or in the presence of a surprise finding of diminished ovarian reserve in a young patient.

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Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome

Cited by 223 publications

References 50 publications

Overexpression of NF90-NF45 Represses Myogenic MicroRNA Biogenesis, Resulting in Development of Skeletal Muscle Atrophy and Centronuclear Muscle Fibers

Overexpression of NF90-NF45 Represses Myogenic MicroRNA Biogenesis, Resulting in Development of Skeletal Muscle Atrophy and Centronuclear Muscle Fibers

High-Throughput Screening to Identify Compounds That Increase Fragile X Mental Retardation Protein Expression in Neural Stem Cells Differentiated From Fragile X Syndrome Patient-Derived Induced Pluripotent Stem Cells

The impact of FMR1 gene mutations on human reproduction and development: a systematic review

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