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Cited by 54Neurogenesis and neuroplasticity mechanismsMicroRNA in disease regulationMultiple Sclerosis Research Studies

Regulation of miRNA 219 and miRNA Clusters 338 and 17-92 in Oligodendrocytes

Open access
de Faria Jr., Omar, Cui, Qiao-Ling, Bin, Jenea M., Bull, Sarah-Jane, Kennedy, Timothy E., Bar-Or, Amit, Antel, Jack P., Colman, David R. +1 more·2012·Frontiers in Genetics
DOI 10.3389/fgene.2012.00046PMC PMC3314186
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Abstract

MicroRNAs (miRs) regulate diverse molecular and cellular processes including oligodendrocyte (OL) precursor cell (OPC) proliferation and differentiation in rodents. However, the role of miRs in human OPCs is poorly understood. To identify miRs that may regulate these processes in humans, we isolated OL lineage cells from human white matter and analyzed their miR profile. Using endpoint RT-PCR assays and quantitative real-time PCR, we demonstrate that miR-219, miR-338, and miR-17-92 are enriched in human white matter and expressed in acutely isolated human OLs. In addition, we report the expression of closely related miRs (miR-219-1-3p, miR-219-2-3p, miR-1250, miR-657, miR-3065-5p, miR-3065-3p) in both rodent and human OLs. Our findings demonstrate that miRs implicated in rodent OPC proliferation and differentiation are regulated in human OLs and may regulate myelination program in humans. Thus, these miRs should be recognized as potential therapeutic targets in demyelinating disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This study profiles microRNA expression in human oligodendrocyte lineage cells acutely isolated from adult white matter and finds that rodent-relevant miR-219, miR-338, and miR-17-92 clusters are expressed and regulated in human oligodendrocytes. The authors propose these microRNAs as conserved regulators of human OPC proliferation/differentiation and potential therapeutic targets in demyelinating disorders.

Key findings

  • miR-219, miR-338, and miR-17-92 are enriched in human white matter and expressed in acutely isolated human oligodendrocytes; miR-219 mature products were at least 5-fold enriched in white matter, miR-338-5p and miR-338-3p >15-fold enriched, and miR-17-92 members >4-fold enriched versus gray matter.
  • During rodent OPC differentiation in vitro, miR-219-5p peaked at DIV5 (>6-fold higher than DIV1) and correlated with PLP expression (Pearson coefficient = 0.999, P = 0.01); miR-338-5p and miR-338-3p increased about 5-fold, while miR-3065-5p was markedly downregulated.
  • In mouse brain development, miR-338-3p showed delayed upregulation (10-fold at P21 and 30-fold at P60 versus P1), and miR-17-92 members were dramatically downregulated in the first postnatal week (about 90% reduced at P7 versus P1).
  • Human A2B5+ versus A2B5− oligodendrocytes showed higher miR-219 levels in A2B5+ cells; miR-338-5p, miR-1250, miR-3065-5p, and miR-657 were significantly downregulated in A2B5− cells, whereas miR-17-92 members showed no significant difference between the two populations.

Methods

  • Human OL lineage cells were isolated from adult white matter surgical resections for non-tumor-related intractable epilepsy, separated by A2B5 magnetic cell sorting into A2B5+ and A2B5− fractions; four independent surgical resections were analyzed in triplicates. Rodent OPCs were cultured from postnatal day 0 Sprague-Dawley rat cortices and matured for 8 h (DIV1), 4 days (DIV5), or 7 days (DIV8).
  • MicroRNA expression was measured by endpoint RT-PCR, stem-loop reverse transcription, multiplex pre-PCR, and quantitative real-time PCR normalized to 18S RNA using the 2−ΔΔCt method and qBase; western blotting was used to confirm PLP upregulation during OPC differentiation.
  • Statistical comparisons used one-way ANOVA with Tukey’s post-test for developmental/culture stages and unpaired Student’s t-test for human sample comparisons.

Limitations

  • Not explicitly stated in the paper; evident from the text: the study is an expression-profiling study and does not functionally manipulate these microRNAs in human OPCs/oligodendrocytes, so the proposed conserved regulatory roles remain inferential.
  • The human white matter enrichment analysis used two independent samples in triplicates, and the acutely isolated human A2B5+/A2B5− comparison used four independent surgical resections, limiting broader generalizability.
  • The authors note discrepancies with a prior human embryonic stem cell-derived oligodendrocyte study and attribute them to differences in sample origin and detection sensitivity; they also state that further investigation into functional contribution is needed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fgene.2012.00046

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 26 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    The miR-338 cluster is expressed in human OLs.

    “In summary, we provide the first evidence that miR-338 cluster is expressed in human OLs, as previously demonstrated in rodents (Lau et al., 2008; Dugas et al., 2010; Zhao et al., 2010).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Lau et al., 2008 source

      The Results section reports miR-338 expression in oligodendrocyte-lineage cells isolated from postnatal rat brains, supporting the rodent finding attributed to Lau et al. The cited paper identifies miR-338, but the passages do not establish expression of a miR-338 cluster as a whole. The sentence presents human OL expression as the citing authors’ new finding, not as Lau et al.’s result. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Dugas et al., 2010 source
    • cites Zhao et al., 2010 source
    • Rests on an assumption: In humans, the miR-338 cluster encodes six different mature miRs (miR-338-5p, miR-338-3p, miR-3065-5p, miR-3065-3p, miR-657, and miR-1250) that are encoded by four independent loci.
  • Premisecitation

    Over-expression of miR-219-5p, miR-338-5p, and miR-338-3p promotes rodent OPC differentiation.

    “In these studies, over-expression of miR-219-5p, miR-338-5p, and miR-338-3p was shown to promote rodent OPC differentiation, indicating that these miRs play important roles during myelination (Lau et al., 2008; Budde et al., 2010; Dugas et al., 2010).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Lau et al., 2008 source

      The Results section on miRNA expression reports that miR-338 increases during oligodendrocyte differentiation and miR-219 is strongly expressed in oligodendrocytes. It does not show that over-expressing these miRNAs promotes rodent OPC differentiation, or establish that effect for the specified 5p and 3p strands. The indexed passages provide no page numbers. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Budde et al., 2010 source
    • cites Dugas et al., 2010 source

      The Results section (‘miR-219 and miR-138 promote OL differentiation’; page unavailable) reports that a miR-219 mimic increased differentiation in purified OPCs. It also reports that miR-338 mimics had no significant effect on OL myelin-gene expression in the assays tested. Thus this paper supports the miR-219 part, but not the claim that over-expression of both miR-338 strands promotes differentiation. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Findingown data

    miR-338-5p, miR-1250, miR-3065-5p, and miR-657 are significantly downregulated in the A2B5− fraction.

    “Quantitative real-time RT-PCR analysis shows that all miR-338 cluster members are detectable in acutely isolate OLs and that miR-338-5p, miR-1250, miR-3065-5p, and miR-657 are significantly downregulated in the A2B5− fraction (Figure 3G).”
    Quote in the paperSubstantial claim
  • Findingown data

    Both A2B5+ and A2B5− oligodendrocytes express the three miR-219 mature products.

    “Quantitative real-time RT-PCR analysis indicates that both A2B5+ and A2B5− OLs express the three miRs and that expression is downregulated as cells mature from A2B5+ to A2B5− OLs (Figure 2I).”
    Quote in the paperSubstantial claim
  • Findingown data

    miR-338-5p appears to be expressed throughout postnatal development.

    “In contrast, miR-338-5p appears to be expressed throughout postnatal development.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 6
  • May combine two claims. 16

  • Classified as probably not a substantial claim.

    Premisecitation

    Expression profiling studies with rodent OLs have reported that several miR species are dramatically regulated during OPC differentiation.

    “Expression profiling studies with rodent OLs have reported that several miR species are dramatically regulated during OPC differentiation (Lau et al., 2008; Budde et al., 2010; Dugas et al., 2010).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Lau et al., 2008 source
    • cites Budde et al., 2010 source
    • cites Dugas et al., 2010 source

  • May combine two claims.

    Findingown data

    miR-219-5p is dramatically upregulated during rat oligodendrocyte precursor cell differentiation in vitro, peaking at DIV5 (>6-fold higher than at DIV1) and dropping by DIV8, but remaining higher than at DIV1.

    “Quantitative real-time RT-PCR shows that miR-219-5p is dramatically upregulated, peaking at DIV5 (>6-fold higher than at DIV1) and dropping by DIV8, but remaining higher than at DIV1 (Figure 2D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-338-5p and miR-338-3p are upregulated and miR-3065-5p is downregulated during rat OPC differentiation in vitro.

    “Quantitative real-time PCR showing upregulation in miR-338-5p and -3p and downregulation of miR-3065-5p during rat OPC differentiation in vitro.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-219-1-3p and miR-219-2-3p are regulated during rodent oligodendrocyte precursor cell differentiation: miR-219-1-3p peaks at DIV5 but returns to DIV1 levels by DIV8, whereas miR-219-2-3p levels remain high through DIV5 to DIV8.

    “Additionally, we found that miR-219-1-3p and 219-2-3p are regulated during rodent OPC differentiation: miR-219-1-3p peaks at DIV5, but returns to DIV1 levels by DIV8 whereas miR-219-2-3p levels remain high through DIV5 to DIV8.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-338-3p and miR-3065-5p were not detected by RT-PCR but were readily amplified using more sensitive real-time RT-PCR.

    “Although miR-338-3p and miR-3065-5p were not detected by RT-PCR, both miRs were readily amplified using more sensitive real-time RT-PCR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The miR-338 cluster is expressed by the human cell line MO3.13 and human A2B5+ OLs.

    “Endpoint RT-PCR followed by polyacrylamide gel electrophoresis showing that miR-338 cluster is expressed by the human cell line MO3.13 and human A2B5+ OLs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-338-5p, miR-3065-5p, and miR-657 are expressed in A2B5+ cells.

    “Using this method, we found that miR-338-5p, miR-1250, and miR-3065-5p are expressed in the MO3.13 cell line whereas miR-338-5p, miR-3065-5p, and miR-657 are expressed in A2B5+ cells (Figure 3F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There is a delayed 10-fold elevation in miR-338-3p expression at P21 and a 30-fold elevation at P60 compared to the levels at P1.

    “Specifically, there is a delayed 10-fold elevation in miR-338-3p expression at P21 and a 30-fold elevation at P60 (compared to the levels at P1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-219-5p and miR-338-5p and miR-338-3p are expressed by human OLs.

    “Importantly, our study is the first to report that miR-219-5p and miR-338-5p and -3p are expressed by human OLs (Figures 2H and 3F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All miR-17-92 miRs are readily detectable by quantitative real-time RT-PCR in both A2B5+ and A2B5− OLs with no significant differences in expression levels between the two populations.

    “All miR-17-92 miRs were readily detectable by quantitative real-time RT-PCR in both A2B5+ and A2B5− OLs with no significant differences in expression levels between the two populations (Figure 4G).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miR-17-92 members are expressed by MO3.13 cells and human A2B5+ OLs.

    “Endpoint RT-PCR followed by polyacrylamide gel electrophoresis showing that miR-17-92 members are expressed by MO3.13 cells and human A2B5+ OLs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When compared to P1, levels at P7 are about 90% reduced and maintained at a similarly low level into adulthood.

    “When compared to P1, levels at P7 are about 90% reduced and maintained at a similarly low level into adulthood (Figure 4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All miRs are expressed in the human OPC cell line (MO3.13) and in acutely isolated A2B5+ OLs.

    “We also used endpoint RT-PCR to study their expression in human OL lineage cells and found that all miRs are expressed in the human OPC cell line (MO3.13) and in acutely isolated A2B5+ OLs (Figure 4F).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    When cultured in the absence of mitogens, oligodendrocyte precursor cells downregulate precursor genes (NG2) and upregulate myelin genes (PLP, MAG, CGT).

    “Prior to the miR expression analysis, we confirmed by endpoint RT-PCR and western blot that when cultured in the absence of mitogens, OPCs downregulate precursor genes (NG2) and upregulate myelin genes (PLP, MAG, CGT; Figure 2C).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The human brain has been examined for miR expression and miR-219-5p, miR-338-5p, miR-338-3p, and members of the miR-17-92 cluster have been reported to be expressed.

    “The human brain has also been examined for miR expression and miR-219-5p, miR-338-5p, miR-338-3p, and members of the miR-17-92 cluster have been reported to be expressed (Barad et al., 2004; Sempere et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Barad et al., 2004 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites Sempere et al., 2004 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    miRs demonstrated to be functionally relevant in rodents perform a conserved function and regulate the proliferation and differentiation of human OPCs.

    “We propose that miRs demonstrated to be functionally relevant in rodents perform a conserved function and regulate the proliferation and differentiation of human OPCs.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    The same miRs controlling OPC differentiation in rodents (miR-219-5p and miR-338-5p and miR-338-3p) may also control OPC differentiation in humans.

    “These findings open the possibility that the same miRs controlling OPC differentiation in rodents (miR-219-5p and miR-338-5p and -3p) may also control OPC differentiation in humans.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Some miR-17-92 members (miR-17-5p, 18a-5p, 19a-3p, 20a-5p, 19b-3p, and 92a-3p) have been implicated in the regulation of OPC proliferation in rodents, but their expression during postnatal brain development and cultured OPC differentiation has not been addressed.

    “Some of them (miR-17-5p, 18a-5p, 19a-3p, 20a-5p, 19b-3p, and 92a-3p, highlighted in red in Figure 4A) have been implicated in the regulation of OPC proliferation in rodents, but their expression during postnatal brain development and cultured OPC differentiation has not been addressed (Budde et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Budde et al., 2010 source
    • Rests on an assumption: The miR-17-92 cluster encodes 12 different miRs in both humans and rodents.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These miRs might play a role in regulating levels of housekeeping transcripts in OLs.

    “Though most miR-17-92 cluster members are downregulated during OPC differentiation, relative expression analysis reveals that these miRs are the most highly expressed miRs in both precursor and mature OLs (Table 1), suggesting that these miRs might play a role in regulating levels of housekeeping transcripts in OLs.”
    Quote in the paperNot a substantial claim
19 of 19

  • The paper relies on this without support.

    The human white matter tissue obtained from surgical resections for intractable epilepsy is representative of normal human white matter.

    “We obtained white matter tissue excised from surgical resections carried out to ameliorate non-tumor-related intractable epilepsy as previously described (Ruffini et al., 2004; Dhaunchak et al., 2010).”

  • The paper relies on this without support.

    In humans, the miR-338 cluster encodes six different mature miRs (miR-338-5p, miR-338-3p, miR-3065-5p, miR-3065-3p, miR-657, and miR-1250) that are encoded by four independent loci.

    “In humans, the miR-338 cluster encodes six different mature miRs (miR-338-5p, miR-338-3p, miR-3065-5p, miR-3065-3p, miR-657, and miR-1250) that are encoded by four independent loci (Figure 3A).”

  • The paper relies on this without support.

    miR-657 and miR-1250 are specific to humans and have not been detected in rodents.

    “Interestingly, these two miRs are specific to humans and have not been detected in rodents.”

  • The paper relies on this without support.

    miR-338-5p and miR-338-3p were previously detected in mature rodent OLs but miR-3065 expression has not been demonstrated before.

    “miRs 338-5p and 338-3p were previously detected in mature rodent OLs but miR-3065 expression has not been demonstrated before.”

  • The paper relies on this without support.

    The miR-17-92 cluster encodes 12 different miRs in both humans and rodents.

    “The miR-17-92 cluster encodes 12 different miRs in both humans and rodents.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • miR-338-3p was approximately 25-fold more abundant in oligodendrocytes than MNs.

    “As expected, miR-338-3p, a miRNA known to be enriched in oligodendrocytes, was ϳ25-fold more abundant in oligodendrocytes than MNs (Zhao et al., 2010;de Faria et al., 2012) (Fig. 2D).”

    From MicroRNA Profiling Reveals Marker of Motor Neuron Disease in ALS Models (2017) · cites this paper as de Faria et al., 2012

    The Results (section “Regulation of the miR-338 cluster during OPC differentiation,” Figure 3E) report that miR-338-3p is enriched in white matter, and the Discussion (“miR regulation in human OLs”) reports its expression in human oligodendrocytes. The source does not compare oligodendrocytes with motor neurons or report a 25-fold difference between them; the citing sentence points to its own Figure 2D for that measurement. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Human-specific miRs are also claimed to be expressed in rodent OLs

    Minor

    The abstract says the listed miRs, including miR-1250 and miR-657, are expressed in both rodent and human OLs. The Results instead describe miR-1250 and miR-657 as human-specific and not detected in rodents.

  • First-time claim conflicts with earlier account of miR-338-3p regulation

    Minor

    The Discussion claims this study demonstrates regulation of miR-338-3p during rodent OPC differentiation for the first time, but the Introduction says earlier work found it more highly expressed in OLs than in precursors.

2 of 2

Cites

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Authors
de Faria Jr., O., Cui, Q.-L., Bin, J. M., Bull, S.-J., Kennedy, T. E., Bar-Or, A., Antel, J. P., Colman, D. R., & Dhaunchak, A. S.
Affiliations
Montreal Neurological Institute and Hospital (CA)
Corresponding author
Dhaunchak, Ajit S.
ORCID
Venue
Frontiers in Genetics
Publisher
Frontiers Media SA
Published
2012
Volume
3
Pages
46-46
ISSN
1664-8021 (ISSN-L)
DOI
10.3389/fgene.2012.00046
PMC
PMC3314186
OpenAlex
W2074103481
Semantic Scholar
f392f33ecf27be49505886df41bd2cd8c93e5140
Cited by
54
References
35
Citations by year
2026: 4 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 5 · 2019: 9 · 2018: 3 · 2017: 3 · 2016: 6 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 1
FWCI
1.19
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Frontiers in Genetics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Molson Foundation
  • Multiple Sclerosis Society of Canada
  • Multiple Sclerosis Society
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
microRNA, miR-219, miR-338, miR-17-92 cluster, oligodendrocyte precursor cells, oligodendrocyte lineage, myelination, miRNA expression profiling, demyelinating disease, therapeutic target

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