Cited by 252MicroRNA in disease regulationNeurogenesis and neuroplasticity mechanismsDevelopmental Biology and Gene Regulation

Identification of Dynamically Regulated MicroRNA and mRNA Networks in Developing Oligodendrocytes

Open access
Lau, Pierre, Verrier, Jonathan D., Nielsen, Joseph A., Johnson, Kory R., Notterpek, Lucia, Hudson, Lynn D.·2008·The Journal of Neuroscience

Abstract

MicroRNAs (miRNAs) play important roles in modulating gene expression at the posttranscriptional level. In postnatal oligodendrocyte lineage cells, the miRNA expression profile (“microRNAome”) contains 43 miRNAs whose expression dynamically changes during the transition from A2B5 + oligodendrocyte progenitor cells to premyelinating GalC + cells. The combination of microRNAome profiling with analyses of the oligodendrocyte transcriptome reveals a target bias for a class of miRNAs which includes miR-9. We show that miR-9 is downregulated during oligodendrocyte differentiation. In addition, miR-9 expression level inversely correlates with the expression of its predicted targets, among which is the peripheral myelin protein PMP22. We found that PMP22 mRNA but not protein is detectable in oligodendrocytes, whereas Schwann cells producing PMP22 protein lack miR-9. We demonstrate that miR-9 interacts with the 3′ untranslated region of PMP22 and downregulates its expression. Our results support models in which miRNAs can act as guardians of the transcriptome.

AI snapshot

Written from the paper’s full text.

TL;DR

This study profiles microRNAs in postnatal rat oligodendrocyte lineage cells and identifies dynamically regulated miRNA–mRNA networks, including a functional interaction between miR-9 and PMP22. It shows that PMP22 mRNA is present in oligodendrocytes but not translated, and that miR-9 down-regulates PMP22 via its 3′UTR.

Key findings

  • 98 miRNAs were reproducibly detected in A2B5+ GalC− oligodendrocyte progenitor cells and A2B5− GalC+ premyelinating oligodendrocytes; 43 miRNAs changed dynamically during differentiation, with 23 down-regulated >2-fold (including miR-9 and miR-124a) and 20 up-regulated >2-fold (including miR-21, miR-152, miR-142-5p/-3p, miR-338, miR-339, and miR-378).
  • Target bias analysis found 37 of 98 miRNAs with target bias in the top or bottom tenth percentile windows; 35 of 37 signatures were negative, while only miR-9 and miR-124a showed positive correlation signatures in oligodendrocytes.
  • PMP22 mRNA was detected in oligodendrocytes and increased ~2-fold during differentiation, but PMP22 protein was not detected in CC1+ oligodendrocytes; Schwann cells lacked mature miR-9 but contained the miR-9 precursor.
  • miR-9 interacted with the PMP22 3′UTR and down-regulated expression: luciferase reporter assays showed ~50% repression (p<0.01), deletion of the AACCAAA repeat blocked miR-9-mediated down-regulation, and miR-9 transfection in Schwann cells reduced PMP22 mRNA by ~30% (p<0.05) with comparable protein reduction (p<0.05).

Methods

  • A2B5+ GalC− OPCs and A2B5− GalC+ oligodendrocytes were FACS-sorted from P7 Sprague-Dawley rat brains; purity was assessed by real-time PCR for neural markers and by CD11b/CD45 FACS analysis.
  • miRNA microarrays and Affymetrix Rat Expression 230 2.0 microarrays were used with four biological replicates; miRNA data were validated by real-time PCR, and target bias was analyzed using TargetScan 4.0 with Fisher’s Exact Test.
  • Functional assays included luciferase reporters containing full-length or fragmented/deleted PMP22 3′UTR in HeLa cells, gelshift assays, and Northern blot, Western blot, and immunofluorescence in rat Schwann cells and postnatal rat brain sections.

Limitations

  • The paper states that its comparison with cortical neuronal cells is preliminary because other neural cells such as neuronal precursors and astrocytes should be included for a more accurate picture.
  • The paper states that 19 additional miRNAs detected by microarray could not be conclusively validated because adequate primers and probes were absent from the multiplex PCR mix.
  • The paper notes that only a few animal miRNA targets are known and that target searches mainly rely on bioinformatic predictions; evident from the text, the miR-9–PMP22 functional validation was performed largely in HeLa and Schwann cells rather than oligodendrocytes, and the target-bias analyses are correlative.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.1932-08.2008

Cites

44 of 44 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 19 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    A repeat of the (AACCAAA) sequence is located in fragment 1 between positions 73 and 134.

    “A closer examination of the 3’UTR reveals that a repeat of the (AACCAAA) sequence is also located in fragment 1 between positions 73 and 134.”
    Quote in the paperSubstantial claim
  • Findingown data

    Only miR-9 and miR-124a predicted targets show a positive correlation signature.

    “In contrast, only miR-9 and miR-124a predicted targets show a positive correlation signature (Fig. 2B and Supplemental Table 4).”
    Quote in the paperSubstantial claim
  • Findingown data

    PMP22 is a predicted target of miR-9.

    “among which is the peripheral myelin protein PMP22”
    Quote in the paperSubstantial claim
  • Findingown data

    The predicted targets of miR-218, miR-449 and miR-487b reverse their correlation signatures from the top A2B5+ GalC− window to the bottom A2B5− GalC+ window.

    “Additionally, we found that the predicted targets of miR-218, miR-449 and miR-487b reverse their correlation signatures from the top A2B5+ GalC− window to the bottom A2B5− GalC+ window.”
    Quote in the paperSubstantial claim
  • Findingown data

    PMP22 mRNA increases ~2 fold during oligodendrocyte differentiation.

    “the quantification revealed an increase of ~2 fold during differentiation (Fig. 3B).”
    • Also stated in: § miRNAs and the control of myelin gene expression · plain
      “Similarly, we observed a ~2 fold increase of PMP22 mRNA level during differentiation, supporting a dynamic regulation of PMP22.”
    Quote in the paperSubstantial claim
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 7
  • May combine two claims.

    Findingown data

    miR-129 and miR-298 are additional neuronal markers.

    “The Venn diagram confirms the preferential expression of miR-128 in mature neurons and reveals two additional neuronal markers: miR-129 and miR-298.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Findingreasoning

    During oligodendrocyte differentiation, miR-335 was down-regulated while miR-21 was strongly up-regulated.

    “During oligodendrocyte differentiation, miR-335 was down-regulated while miR-21 was strongly up-regulated, in line with the antagonistic action of miR-335 on miR-21.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Findingown data

    The A2B5+ GalC− population has low abundance of neuronal and astrocyte markers and less than 2% contaminating microglial cells based on CD11b expression.

    “Additionally, the real-time PCR analysis of purified A2B5+ GalC− cells shows the low abundance of neuronal and astrocyte markers and the FACS analysis reveals the weak presence of contaminating microglial cells (less than 2%, based on CD11b expression, Supplemental Fig. 1B).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    The second class of inversions is defined by a reversal from negative to positive correlations and contains only miR-9 and miR-124a.

    “The second class is defined by a reversal from negative to positive correlations and only contains miR-9 and miR-124a (Fig. 2C).”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Findingown data

    Ten miRNAs are down-regulated more than 2 fold, and only the predicted targets of miR-9 and miR-124a are associated with a reversal of correlation signatures from the bottom A2B5+ GalC− window to the top A2B5− GalC+ window.

    “Furthermore, 10 miRNAs are down-regulated more than 2 fold and only the predicted targets of miR-9 and miR-124a are associated with a reversal of the correlation signatures from the bottom A2B5+ GalC− window to the top A2B5− GalC+ window.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    These six miRNAs have negative target bias in the oligodendrocyte lineage but possess significant positive correlation signatures in neuronal cells.

    “Interestingly, these six miRNAs have negative target bias in the oligodendrocyte lineage but possess significant positive correlation signatures in neuronal cells.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    Postnatal oligodendrocytes in the corpus callosum of rat brains are labeled with the CC1 antibody and not with the PMP22 antibody.

    “The postnatal oligodendrocytes in the corpus callosum of rat brains are labeled with the CC1 antibody and not with the PMP22 antibody (Fig. 3C).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    The A2B5− GalC+ population contains approximately 5% CD11b positive and 7% CD45 positive cells.

    “The FACS analysis reveals that ~5% of the A2B5− GalC+ cells are CD11b positive and ~7% are CD45 positive (Supplemental Fig. 1B).”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Findingown data

    Only fragments 1 (positions 1-157) and 2 (positions 158-498) of the PMP22 3'UTR support miR-9-mediated down-regulation, while fragment 3 (positions 499-1127) does not.

    “Only fragment 1 (positions 1-157 relative to the stop codon) and fragment 2 (positions 158–498) support the down-regulation (p<0.01 for fragments 1 and 2, Student’s t-test), while fragment 3 (positions 499–1127) does not.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The absence of PMP22 protein in oligodendrocytes is consistent with a previous proteomic study that did not reveal PMP22 in CNS myelin.

    “The absence of PMP22 protein in oligodendrocytes is consistent with a previous proteomic study that extensively characterized proteins of CNS myelin and did not reveal PMP22 (Taylor et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Taylor et al., 2004 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    As a positive control, the PMP22 antibody clearly stains neuroepithelial junctions in adjacent sections.

    “As positive control, the PMP22 antibody clearly stains neuroepithelial junctions in adjacent sections (Fig. 3D) (Roux et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Roux et al., 2004 source

      Not checked in the free run.

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

    Interpretationcitation

    miR-9 expression is increased in oligodendroglioma compared to normal adult brain, suggesting a potential role in neoplasia.

    “In oligodendroglioma, miR-9 expression is increased when compared to normal adult brain, suggesting a potential role in neoplasia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nelson et al., 2006

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductnone given

    The comparison is preliminary since other neural cells such as neuronal precursors and astrocytes should be included to obtain a more accurate picture.

    “However, the comparison is preliminary since other neural cells such as neuronal precursors and astrocytes should be included to obtain a more accurate picture.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In human and rodents, there are three copies of mir-9 and only two are functional.

    “In human and rodents, there are three copies of mir-9 and only two are functional (Krichevsky et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Krichevsky et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The predicted binding site of miR-9 is located in fragment 2 (positions 421-443) and may explain the response obtained with this fragment.

    “The predicted binding site (BS) of miR-9 is located in fragment 2 (positions 421–443) and may explain the response obtained with this fragment.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Interpretationown data

    In vivo experiments show that PMP22 is transcribed in oligodendrocytes but no protein is synthesized.

    “Altogether, the in vivo experiments show that PMP22 is transcribed in oligodendrocytes, however no protein is synthesized.”
    • Also stated in: § miRNAs and the control of myelin gene expression · plain
      “Notably, we found that PMP22 mRNA is detected in oligodendrocytes and that the protein is not expressed.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Interpretationreasoning

    The maturation of neuroblasts is associated with a decrease in the expression level of miR-9, and its down-regulation during oligodendrocyte development is consistent with a role in proliferating neural cells of the brain.

    “Furthermore, the maturation of neuroblasts is associated with a decrease in the expression level of miR-9, and its down-regulation during the course of oligodendrocyte development is consistent with a role in the proliferating neural cells of the brain.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The expression of miR-9 is very high in neuroblasts and glioblasts of fetal brain.
    • Rests on an assumption: The maturation of neuroblasts is associated with a decrease in the expression level of miR-9.
  • May combine two claims.

    Interpretationown data

    9 of 16 miRNAs, including miR-9, may affect the expression level of their predicted targets and are excellent candidates for searching functional targets using DNA microarray techniques.

    “Overall, this analysis shows that 9 of 16 miRNAs, including miR-9, may affect the expression level of their predicted targets and thus would be excellent candidates to consider when searching for functional targets using DNA microarray techniques.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Interpretationcitation

    The miRNAs in the second class may serve as buffers to silence genetic noise of unwanted transcripts arising from 'leaky' transcription, and such a role has been attributed to miR-9.

    “The miRNAs in the second class may serve as buffers to silence the genetic noise of unwanted transcripts arising from “leaky” transcription (Hornstein and Shomron, 2006) and such a role has been attributed to miR-9 (Li et al., 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hornstein and Shomron, 2006 source

      Not checked in the free run.

    • cites Li et al., 2006

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Interpretationcitation

    A similar post-transcriptional event may also explain the expression pattern of other brain-enriched miRNAs such as miR-138.

    “A similar post-transcriptional event may also explain the expression pattern of other brain-enriched miRNAs such as miR-138 (Obernosterer et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Obernosterer et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    19 additional miRNAs were unambiguously detected by miRNA microarrays but their validation remained inconclusive due to absence of adequate primers and probes.

    “Although 19 additional miRNAs were unambiguously detected by miRNA microarrays (Supplemental Table 2), their validation essentially remained inconclusive due to the absence of adequate primers and probes in the multiplex PCR mix.”
    Quote in the paperNot a substantial claim
  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    This work provides an important step toward the functional identification of miRNAs and how they interact with their targets to control the oligodendrocyte identity.

    “Overall, this work provides an important step toward the functional identification of miRNAs and how they interact with their targets to control the oligodendrocyte identity.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Interpretationcitation

    The miRNAs in the first class are in line with studies showing that the expression level of predicted targets is generally higher before differentiation and that some miRNAs dampen output of transcriptionally down-regulated mRNAs to facilitate faster transition in gene expression.

    “The miRNAs in the first class are in line with studies showing that the expression level of the predicted targets is generally higher before differentiation, and that some miRNAs dampen the output of the transcriptionally down-regulated mRNAs to facilitate a faster transition in gene expression (Stark et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stark et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The comparison supports the main expression of miR-124a in proliferating neural cells since miR-124a is shut-down during oligodendrocyte lineage progression, mirroring its down-regulation when neuronal cells differentiate.

    “The comparison also supports the main expression of miR-124a in proliferating neural cells since miR-124a is shut-down during oligodendrocyte lineage progression, mirroring its down-regulation when neuronal cells differentiate.”
    Quote in the paperNot a substantial claim
24 of 24
  • The paper relies on this without support.

    In vivo miRNA expression profiles of defined neural populations have not been reported yet.

    “In vivo miRNA expression profiles of defined neural populations have not been reported yet.”
  • The paper relies on this without support.

    The miRNA expression profiles of specific neural populations (neurons, oligodendrocytes and astrocytes) have not been fully addressed.

    “the miRNA expression profiles of specific neural populations (neurons, oligodendrocytes and astrocytes) have not been fully addressed.”
  • The paper relies on this without support.

    NDRG1 has been previously reported to be expressed in oligodendrocytes and not PMP22.

    “NDRG1 has been previously reported to be expressed in oligodendrocytes and not PMP22, thus making PMP22 an attractive candidate target of miR-9.”
  • The paper relies on this without support.

    miR-9 is enriched in the brain and is conserved during evolution.

    “miR-9 is enriched in the brain and is conserved during evolution, suggesting some important functions in neural cells.”
  • The paper relies on this without support.

    The expression of miR-9 is very high in neuroblasts and glioblasts of fetal brain.

    “The expression of miR-9 is very high in neuroblasts and glioblasts of fetal brain.”
  • The paper relies on this without support.

    The maturation of neuroblasts is associated with a decrease in the expression level of miR-9.

    “Furthermore, the maturation of neuroblasts is associated with a decrease in the expression level of miR-9”
6 of 6

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?

  • 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).”

    From Regulation of miRNA 219 and miRNA Clusters 338 and 17-92 in Oligodendrocytes (2012) · cites this paper as Lau et al., 2008

  • Regulation of miR-17-92 cluster expression during the OPC/OL transition was not reported in previous microarray studies.

    “In previous microarray studies, regulation of miR-17-92 cluster expression during the OPC/OL transition was not reported (Lau et al., 2008).”

    From Regulation of miRNA 219 and miRNA Clusters 338 and 17-92 in Oligodendrocytes (2012) · cites this paper as Lau et al., 2008

  • 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).”

    From Regulation of miRNA 219 and miRNA Clusters 338 and 17-92 in Oligodendrocytes (2012) · cites this paper as Lau et al., 2008

  • These miRs play important roles during myelination.

    “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).”

    From Regulation of miRNA 219 and miRNA Clusters 338 and 17-92 in Oligodendrocytes (2012) · cites this paper as Lau et al., 2008

  • 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).”

    From Regulation of miRNA 219 and miRNA Clusters 338 and 17-92 in Oligodendrocytes (2012) · cites this paper as Lau et al., 2008

Cites

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Authors
Lau, P., Verrier, J. D., Nielsen, J. A., Johnson, K. R., Notterpek, L., & Hudson, L. D.
Affiliations
  • National Institutes of Health (US)
  • University of Florida (US)
Corresponding author
Hudson, Lynn D.
Venue
The Journal of Neuroscience
Published
2008-11-05
Volume
28
Issue
45
Pages
11720-11730
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2047606645
Cited by
252
References
44
Citations by year
2026: 3 · 2025: 6 · 2024: 9 · 2023: 12 · 2022: 10 · 2021: 6 · 2020: 11 · 2019: 13 · 2018: 5 · 2017: 16 · 2016: 12 · 2015: 18 · 2014: 25 · 2013: 19 · 2012: 20
FWCI
7.48
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Muscular Dystrophy Association
  • McKnight Foundation
  • Johns Hopkins University
  • European Molecular Biology Laboratory
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS041012, Z01NS002528)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
microRNA, miR-9, oligodendrocyte differentiation, oligodendrocyte precursor cells, PMP22, 3' untranslated region, post-transcriptional regulation, miRNAome, transcriptome, Schwann cells, microRNA target regulation
MeSH terms
Animals, Animals, Newborn, Brain, Cells, Cultured, Galactosylceramides, Gangliosides, Myelin Proteins, Oligodendroglia, RNA, Messenger, Sciatic Nerve, Transfection, Antigens, CD, Rats, Sprague-Dawley, Nonlinear Dynamics, Gene Expression Regulation, Developmental, Computational Biology, MicroRNAs, Microarray Analysis, Green Fluorescent Proteins, Rats

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