Mir-17∼92 Governs Motor Neuron Subtype Survival by Mediating Nuclear PTEN

Tung, Ying Tsen; Lu, Ya Lin; Peng, Kuan Chih; Yen, Ya-Ping; Chang, Mien; Li, Joye; Jung, Hye Ra; Thams, Sebastian; Huang, Yuan; Hung, Jui-Hung; Chen, Jun-An

doi:10.1016/j.celrep.2015.04.050

Cited by 24 publications

(48 citation statements)

References 61 publications

(101 reference statements)

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“…Further investigation is needed to understand the mechanism involved in down-regulation of USP2 by miR-17. In agreement with our results, mir-17-92 cluster has previously been shown to targets E3 ubiquitin ligases, thereby affecting PTEN subcellular localization through monoubiquitination of limb-innervating lateral motor neurons (46). …”

Section: Discussionsupporting

confidence: 93%

MicroRNA-17 Suppresses TNF-α Signaling by Interfering with TRAF2 and cIAP2 Association in Rheumatoid Arthritis Synovial Fibroblasts

Akhtar

Singh

Ahmed

2016

The Journal of Immunology

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TNF-α is a major cytokine implicated in rheumatoid arthritis (RA). TNF-α expression is shown to be regulated at transcriptional as well as posttranscriptional levels. However, the impact of changes in microRNA (miRNA) expression on posttranslational processes involved in TNF-α signaling networks is not well-defined in RA. Here we evaluated the effect of miR-17, a member of miR-17-92~ cluster, on TNF-α signaling pathway in human RA synovial fibroblasts (RASFs). We demonstrated that miR-17 expression was significantly low in RA serum, SFs, and synovial tissues as well as in the serum and joints of adjuvant-induced arthritis rats. RNA sequencing analysis showed modulation of 664 genes by pre-miR-17 in human RASFs. Ingenuity pathway analysis of RNA sequencing data identified the ubiquitin proteasome system (UPS) in TNF-α signaling pathway as a primary target of miR-17. Western blot analysis confirmed the reduction of TRAF2, cIAP1, cIAP2, USP2, and PSMD13 expression by miR-17 in TNF-α-stimulated RASFs. Immunoprecipitation assays showed that miR-17 restoration increased the K48-linked polyubiquitination of TRAF2, cIAP1, and cIAP2 in TNF-α-stimulated RASFs. Thus, destabilization of TRAF2 by miR-17 reduced the ability of TRAF2 to associate with cIAP2, thereby resulting in the downregulation of TNF-α-induced NF-κBp65, c-Jun, and STAT3 nuclear translocation and the production of IL-6, IL-8, MMP-1, and MMP-13 in human RASFs. In conclusion, this study provides evidence for the role of miR-17 as a negative regulator of TNF-α signaling by modulating the protein ubiquitin processes in RASFs.

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Section: Discussionsupporting

confidence: 93%

MicroRNA-17 Suppresses TNF-α Signaling by Interfering with TRAF2 and cIAP2 Association in Rheumatoid Arthritis Synovial Fibroblasts

Akhtar

Singh

Ahmed

2016

The Journal of Immunology

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“…Consequently, Hoxc8 further maintains the expression of mir-27 to generate a coherent feed-forward inhibition pathway to maintain the mutually exclusive Hoxa5-Hoxc8 sharp boundary10. This is similar to our previous study showing Olig2/Irx3/ mir-17-3p constitutes a feed-forward circuit to carve the p2/pMN boundary28. We speculate that the relationship between the miRNA-induced protein expression delay and the robust boundary formation could be a general design principle for other miRNA circuits.…”

Section: Discussionsupporting

confidence: 88%

“…In some cases, caudal LMC neuron differentiation was acquired by including 100 ng ml −1 bFGF together with reduced concentrations of RA and SAG at Day2 of differentiation2829.…”

Section: Methodsmentioning

confidence: 99%

“…Several Hox transcripts are localized in broader domains than their corresponding proteins2122, indicating that post-transcriptional regulation is involved in the refinement of the spatiotemporal Hox collinearity features reflected at transcriptional levels in the developing spinal cord. As we and others have demonstrated that miRNAs are critical in dorsoventral progenitor patterning, as well as motor neuron subtype diversification in the spinal cord232425262728, here we aimed to test whether miRNAs might prevent precocious Hox protein expression until neurons differentiate and whether this regulation is functionally important.…”

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confidence: 99%

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MicroRNA filters Hox temporal transcription noise to confer boundary formation in the spinal cord

Hong

Tung

et al. 2017

Nat Commun

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The initial rostrocaudal patterning of the neural tube leads to differential expression of Hox genes that contribute to the specification of motor neuron (MN) subtype identity. Although several 3′ Hox mRNAs are expressed in progenitors in a noisy manner, these Hox proteins are not expressed in the progenitors and only become detectable in postmitotic MNs. MicroRNA biogenesis impairment leads to precocious expression and propagates the noise of Hoxa5 at the protein level, resulting in an imprecise Hoxa5-Hoxc8 boundary. Here we uncover, using in silico simulation, two feed-forward Hox-miRNA loops accounting for the precocious and noisy Hoxa5 expression, as well as an ill-defined boundary phenotype in Dicer mutants. Finally, we identify mir-27 as a major regulator coordinating the temporal delay and spatial boundary of Hox protein expression. Our results provide a novel trans Hox-miRNA circuit filtering transcription noise and controlling the timing of protein expression to confer robust individual MN identity.

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“…This cluster targets an E3 ubiguitin ligase to regulate monoubiquitination of PTEN, which determines the subcellular location of the protein. By this mechanism, miR17-92 is able to regulate motor neuron vulnerability in ALS [145,146]. In another example, treatments to suppress miR-155, which is upregulated in ALS model rodents and patient spinal cord, improve survival in SOD1 G93A rodent models mainly by blocking miR-155 function in microglia, astrocytes and neurons [22,147].…”

Section: Ncrnas In Other Mechanisms Of Ad Pathogenesismentioning

confidence: 99%

Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases

2020

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Recent transcriptome analyses have revealed that noncoding RNAs (ncRNAs) are broadly expressed in mammalian cells and abundant in the CNS, with tissue and cell type-specific expression patterns. Moreover, ncRNAs have been found to intricately and dynamically regulate various signaling pathways in neurodegeneration. As such, some antisense transcripts and microRNAs are known to directly affect neurodegeneration in disease contexts. The functions of ncRNAs in pathogenesis are unique for each disorder, as are the pertinent networks of ncRNA/miRNA/ mRNA that mediate these functions. Thus, further understanding of ncRNA biogenesis and effects might aid the discovery of diagnostic biomarkers or development of effective therapeutics for neurodegenerative disorders. Here, we review the ncRNAs that have so far been identified in major neurodegenerative disease etiology and the mechanisms that link ncRNAs with disease-specific phenotypes, such as HTT aggregation in HD, α-synuclein in PD, and Aβ plaques and hyperphosphorylated Tau in AD. We also summarize the known lncRNA/miRNA/mRNA networks that participate in neurodegenerative diseases, and we discuss ncRNA-related treatments shown to delay disease onset and prolong lifespan in rodent models.

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Mir-17∼92 Governs Motor Neuron Subtype Survival by Mediating Nuclear PTEN

Cited by 24 publications

References 61 publications

MicroRNA-17 Suppresses TNF-α Signaling by Interfering with TRAF2 and cIAP2 Association in Rheumatoid Arthritis Synovial Fibroblasts

MicroRNA-17 Suppresses TNF-α Signaling by Interfering with TRAF2 and cIAP2 Association in Rheumatoid Arthritis Synovial Fibroblasts

MicroRNA filters Hox temporal transcription noise to confer boundary formation in the spinal cord

Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases

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