miRNA malfunction causes spinal motor neuron disease

Haramati, Sharon; Chapnik, Elik; Sztainberg, Yehezkel; Eilam, Raya; Zwang, Raaya; Gershoni, Noga; McGlinn, Edwina; Heiser, Patrick W.; Wills, Anne Marie; Wirguin, Itzhak; Rubin, Lee L.; Misawa, Hidemi; Tabin, Clifford J.; Brown, Robert H.; Chen, Alon; Hornstein, Eran

doi:10.1073/pnas.1006151107

Cited by 290 publications

(266 citation statements)

References 78 publications

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“…However, mislocalization of TDP-43 due to accumulation in cytoplasmic aggregates probably reduces the processing of TDP-43-regulated miRNAs by Drosha and Dicer. The knockout of Dicer specifically in postmitotic postnatal motor neurons in mice induces locomotor dysfuction due to the presence of a reduced number of motor neurons (30), indicating that a subset of miRNAs is essential for long-term survival of spinal motor neurons. Among the TDP-43-regulated miRNAs identified in this study, miR-132-3p is highly enriched in neurons and promotes neuronal outgrowth in vitro and in vivo by reducing the levels of the GTPase-activating protein, p250GAP (26,27).…”

Section: Discussionmentioning

confidence: 99%

TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes

Kawahara

Mieda-Sato

2012

Proc. Natl. Acad. Sci. U.S.A.

357

366

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Although aberrant microRNA (miRNA) expression is linked to human diseases including cancer, the mechanisms that regulate the expression of each individual miRNA remain largely unknown. TAR DNA-binding protein-43 (TDP-43) is homologous to the heterogeneous nuclear ribonucleoproteins (hnRNPs), which are involved in RNA processing, and its abnormal cellular distribution is a key feature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases. Here, we show that TDP-43 facilitates the production of a subset of precursor miRNAs (pre-miRNAs) by both interacting with the nuclear Drosha complex and binding directly to the relevant primary miRNAs (primiRNAs). Furthermore, cytoplasmic TDP-43, which interacts with the Dicer complex, promotes the processing of some of these premiRNAs via binding to their terminal loops. Finally, we show that involvement of TDP-43 in miRNA biogenesis is indispensable for neuronal outgrowth. These results support a previously uncharacterized role for TDP-43 in posttranscriptional regulation of miRNA expression in both the nucleus and the cytoplasm.M icroRNAs (miRNAs), small noncoding RNAs of ∼20-22 nt, have emerged as novel regulatory factors of gene expression (1). The expression of each individual miRNA is tightly regulated in a development-and cell-specific manner through transcriptional or posttranscriptional control. As a result, miRNAs can act as regulatory switches for development, organogenesis, and cellular differentiation and control distinct functions that are required for the maintenance of different cell subtypes. Moreover, the altered expression of certain miRNAs is involved in the pathogenesis of developmental abnormalities and human diseases such as cancer and Parkinson's disease (2, 3). As a consequence, understanding the mechanisms that regulate the expression of each individual miRNA is essential to elucidate the molecular pathogenesis of human diseases.MiRNAs are generated from long primary transcripts, termed pri-miRNAs, which consist of a short dsRNA region and a loop. The nuclear Drosha complex cleaves pri-miRNAs to release intermediate precursors that are termed pre-miRNAs. Pre-miRNAs are then transported by Exportin-5 into the cytoplasm where they are cleaved further by the Dicer complex to generate mature miRNAs. Finally, mature miRNAs are incorporated into the RNA-induced silencing complex (RISC), after which they can hybridize to the 3′-untranslated region (UTR) of their target mRNAs to repress translation or degrade these mRNAs (4). DGCR8 is a partner protein that is indispensable for the processing of pri-miRNAs by Drosha (5). In addition, recent work has identified multiple proteins that modulate the processing of specific miRNAs by interacting with the Drosha complex or by binding directly to pri-miRNAs or both (6, 7). Compared with the number of regulatory proteins that are involved in Drosha cleavage, only a few proteins have been identified that regulate the processing of pre-miRNAs by Dicer (6, 7)....

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Section: Discussionmentioning

confidence: 99%

TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes

Kawahara

Mieda-Sato

2012

Proc. Natl. Acad. Sci. U.S.A.

357

366

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“…These small, noncoding RNAs modulate gene expression at the post-transcriptional level and are responsible for regulating many biological processes including differentiation, 1 apoptosis, proliferation and cell-fate determination. 2 Considering the role miRNAs have in regulating these cellular processes, it is not surprising that dysregulation of miRNAs has been implicated in a variety of pathologies, such as inflammatory and autoimmune diseases, neurological disorders, 3 myocardial disease, 4 as well as several types of cancer. 5 Recently, evidence has shown that miRNAs also have a role in viral infections, which include invoking an antiviral response; alternatively, the viruses themselves can encode miRNAs or regulate endogenous host miRNAs, which aid in the infection process.…”

Section: Introductionmentioning

confidence: 99%

Chemical modification and design of anti-miRNA oligonucleotides

2011

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Antisense techniques have been employed for over 30 years to suppress expression of target RNAs. Recently, microRNAs (miRNAs) have emerged as a new class of small, non-coding, regulatory RNA molecules that widely impact gene regulation, differentiation and disease states in both plants and animals. Antisense techniques that employ synthetic oligonucleotides have been used to study miRNA function and some of these compounds may have potential as novel drug candidates to intervene in diseases where miRNAs contribute to the underlying pathophysiology. Anti-miRNA oligonucleotides (AMOs) appear to work primarily through a steric blocking mechanism of action; these compounds are synthetic reverse complements that tightly bind and inactivate the miRNA. A variety of chemical modifications can be used to improve the performance and potency of AMOs. In general, modifications that confer nuclease stability and increase binding affinity improve AMO performance. Chemical modifications and/or certain structural features of the AMO may also facilitate invasion into the miRNA-induced silencing complex. In particular, it is essential that the AMO binds with high affinity to the miRNA 'seed region', which spans bases 2-8 from the 5¢-end of the miRNA.

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“…2,3,12,13 Therefore, miRNAs are involved in a wide range of biological functions, including cellular proliferation, differentiation, angiogenesis, apoptosis, and metastatic potential. 2,[12][13][14][15][16][17] Aberrant miRNA expression has been reported to be involved in the pathogenesis of Alzheimer's disease, 18 cardiovascular disease, 19 spinal motor neuron anomalies, 20 and numerous others. 2 Furthermore, deregulated expression of miRNAs has been identified in a variety of human malignancies, 12,13,[21][22][23][24][25][26][27][28][29] suggesting that miRNAs function as potential oncogenic factors or tumor suppressors, depending on the cell type or tissue investigated and their target genes.…”

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confidence: 99%