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Cited by 177Neurogenesis and neuroplasticity mechanismsMultiple Sclerosis Research StudiesMicroRNA in disease regulation

miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS

Open access
Wang, Haibo, Moyano, Ana Lis, Ma, Zhangyan, Deng, Yaqi, Lin, Yifeng, Zhao, Chuntao, Zhang, Liguo, Jiang, Minqing +8 more·2017·Developmental Cell
DOI 10.1016/j.devcel.2017.03.001PMC PMC5569304
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Abstract

A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.

AI snapshot

Written from the paper’s full text.

TL;DR

This study shows that miR-219 is required for CNS myelination and remyelination and that increasing its levels promotes oligodendrocyte maturation and myelin repair in mouse demyelination and EAE models. It also identifies stage-specific miR-219 targets, including Lingo1 and Etv5, and demonstrates cooperation with miR-338.

Key findings

  • Germline loss of both miR-219 genes caused neonatal lethality, while oligodendrocyte-lineage conditional double mutants developed tremors around postnatal week 3, most died near 4 months, and showed reduced MBP/Plp1 expression, fewer CC1+ mature oligodendrocytes, fewer myelinated axons, and higher g ratios at P28 and P215; OPC numbers were largely unchanged.
  • miR-338 single mutants had no obvious myelination defect, but combining miR-338 loss with miR-219 conditional loss worsened hypomyelination, indicating cooperative regulation of oligodendrocyte maturation.
  • Adult inducible miR-219 deletion impaired remyelination after lysolecithin injury, whereas Cnp1-driven miR-219 overexpression produced about 3-fold higher miR-219 at P7, caused precocious MBP+ oligodendrocytes, and improved remyelination; miR-219 mimic delivery also enhanced repair after lysolecithin and improved motor recovery in MOG35-55 EAE, with more CC1+/Plp1+ oligodendrocytes and preserved axons.
  • Integrated RNA-seq and biotinylated miRNA pull-down identified roughly 24 candidate targets in OPCs and 67 in differentiating oligodendrocytes, including Lingo1 as the most enriched candidate; Nfia, Nfib, and Etv5 were also implicated, and knocking down Lingo1 and Etv5 partially rescued differentiation of miR-219-deficient OPCs, with dual knockdown more effective.

Methods

  • Mouse genetics used floxed miR-219-1/2 and miR-338 alleles with CAG-Cre, Olig1-Cre, and Plp-CreERt lines, plus a Cnp1-miR-219 transgenic line; demyelination was modeled by lysolecithin injection and EAE by MOG35-55 immunization.
  • Primary rat and mouse OPC cultures were used for differentiation assays, siRNA knockdown, luciferase reporter validation, and biotin-tagged miR-219 pull-down.
  • RNA-seq was performed on P12 optic nerves, miRNA mimic-treated OPCs/immature oligodendrocytes, and pull-down samples; histology, in situ hybridization, electron microscopy, qRT-PCR, and blinded quantification were used, with t tests or ANOVA and p < 0.05 as significance threshold.

Limitations

  • Stated in the paper: miR-219 is mainly expressed in differentiating oligodendrocytes with low OPC expression, so its OPC-specific function and remyelination role require PDGFRα+ OPC-specific Cre lines; in EAE, indirect effects on inflammatory cells, trafficking, or paracrine glial support cannot be excluded, and the oligodendrocyte cell-autonomous contribution in EAE is not fully resolved.
  • Evident from the text: several target-rescue experiments were performed in cultured OPCs rather than in vivo, and the study reports no direct human MS therapeutic data; sample sizes were not predetermined, though the authors state they resemble field norms.

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

Integrity signals

Registry

Crossref · 10.1016/j.devcel.2017.03.001

Cites

57 of 57 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

1 of 25 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    miR-219 and miR-338 are preferentially and abundantly expressed in mature oligodendrocytes.

    “Among them, miR-219 and miR-338 are preferentially and abundantly expressed in mature OLs (Dugas et al., 2010; Lau et al., 2008; Zhao et al., 2010).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Dugas et al., 2010 source

      Not checked in the free run.

    • cites Lau et al., 2008 source

      The Results section reports strong miR-219 expression in oligodendrocytes and increased miR-338 expression during differentiation. The Discussion says miR-338 may be preferentially expressed in differentiating oligodendrocytes, but calls that comparison preliminary. These passages do not establish that both miRNAs are preferentially and abundantly expressed specifically in mature oligodendrocytes; page numbers were not provided. (LLM, conf=0.86)

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

      Not checked in the free run.

  • Findingown data

    There was a striking reduction in the number of CC1+ mature oligodendrocytes in miR-219-dCKO mice.

    “there was a striking reduction in the number of CC1+ mature OLs (Figures 2G–2I and 2K)”
    Quote in the paperSubstantial claim
  • Findingown data

    In vivo delivery of miR-219 improves clinical symptoms in the animal model of MS.

    “improves clinical symptoms in the animal model of MS”
    Quote in the paperSubstantial claim
  • Findingown data

    Most miR-219-dCKO mice died around 4 months of age.

    “Most miR-219-dCKO mice died around 4 months of age”
    Quote in the paperNot a substantial claim
  • Findingown data

    Expression of Mbp and Plp1 was substantially diminished in miR-219-dCKO mice at P7 and P28.

    “In situ hybridization analysis of the cortex, corpus callosum, and spinal cord at P7 and at P28 indicated that expression of Mbp and Plp1 was substantially diminished in miR-219-dCKO mice”
    Quote in the paperSubstantial claim
  • May combine two claims. 15
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    miR-219 is essential and sufficient for timely remyelination.

    “Our in vivo gain- and loss-of-function studies demonstrate that miR-219 is both essential and sufficient for timely remyelination”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-219 alleles are critical for CNS myelination and remyelination after injury.

    “we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In vivo delivery of miR-219 enhances OL remyelination following toxin-induced acute demyelination and in immune-mediated chronic demyelination in EAE.

    “in vivo delivery of miR-219 enhances OL remyelination not only following toxin-induced acute demyelination but also in immune-mediated chronic demyelination in EAE”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    miR-219 likely promotes the differentiation of postmitotic OPCs without significantly intervening OPC proliferation during the proliferation phase after injury.

    “our data suggest that miR-219 likely promotes the differentiation of postmitotic OPCs without significantly intervening OPC proliferation during the proliferation phase after injury.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-338−/− mice were born at the normal Mendelian ratio and were phenotypically similar to wild-type mice.

    “miR-338−/− mice were born at the normal Mendelian ratio and were phenotypically similar to wild-type mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-219-dCKO mice developed tremors beginning around postnatal week 3 and exhibited severe seizures as well as ataxia in adulthood.

    “The miR-219-dCKO mice developed tremors beginning around postnatal week 3, the peak period of myelinogenesis, and exhibited severe seizures as well as ataxia in adulthood”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice.

    “Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Injury may lead to the accumulation of OPCs, which could undergo apoptosis if they are unable to differentiate.

    “Since injury stimulates OPC proliferation, it may lead to the accumulation of OPCs, which could undergo apoptosis if they are unable to differentiate.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Injury stimulates OPC proliferation.

  • May combine two claims.

    Premisecitation

    In MS lesions, OPCs are recruited but fail to differentiate into myelinating OLs.

    “In MS lesions, OPCs are recruited but fail to differentiate into myelinating OLs, suggesting that remyelination is blocked at the differentiation and remyelination stage rather than during OPC recruitment (Chang et al., 2002; Kuhlmann et al., 2008; Wolswijk, 1998).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chang et al., 2002 source
    • cites Kuhlmann et al., 2008 source

      Not checked in the free run.

    • cites Wolswijk, 1998 source

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

  • May combine two claims.

    Interpretationreasoning

    Elevation of miR-219 expression in accumulated OPCs in demyelinating lesions likely down-regulates PDGFRα and promotes OPC differentiation.

    “The elevation of miR-219 expression in the accumulated OPCs in demyelinating lesions (Figure S4C) likely down-regulates PDGFRα and promotes OPC differentiation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Injury stimulates OPC proliferation.

  • May combine two claims.

    Interpretationown data

    miR-219 deficiency does not affect OPC formation, but inhibits their differentiation during development.

    “suggesting that miR-219 deficiency does not affect OPC formation, but inhibits their differentiation during development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    miR-219 is both necessary and sufficient to promote OL myelination and remyelination after demyelination.

    “we demonstrate that miR-219 is both necessary and sufficient to promote OL myelination and remyelination after demyelination”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisecitation

    Functional recovery in MS patients will likely hinge on therapies that promote myelin regeneration.

    “Functional recovery in MS patients will likely hinge on the therapies that promote myelin regeneration (Deshmukh et al., 2013; Franklin and Gallo, 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Deshmukh et al., 2013 source

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

    • cites Franklin and Gallo, 2014 source

  • May combine two claims.

    Premisecitation

    In vitro culture studies suggest miR-219 is critical for OPC differentiation and acts through suppressing expression of OL differentiation inhibitors, including PDGFRα, Sox6, and Zfp238.

    “In vitro culture studies suggest that miR-219 is critical for OPC differentiation and acts through suppressing expression of OL differentiation inhibitors, including PDGFRα, Sox6, and Zfp238, predicted by computational algorithms (Dugas et al., 2010; Zhao et al., 2010);”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Dugas et al., 2010 source

      Not checked in the free run.

    • cites Zhao et al., 2010 source

      Not checked in the free run.

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

    Premisecitation

    miRNAs play a critical role especially under pathologic conditions such as injury and stress.

    “miRNAs play a critical role especially under pathologic conditions such as injury and stress (Leung and Sharp, 2010; Mendell and Olson, 2012)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Leung and Sharp, 2010 source

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

    • cites Mendell and Olson, 2012 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Histological quantitative analyses were performed in a blinded manner to experimental groups.

    “The quantitative analyses were performed in a blinded manner to the experimental groups.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    EAE mice were randomized into treatment groups after disease peak.

    “they were randomized into 2 treatment groups”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    For the miR-219 treatment study in mice, animal groups were randomized during treatment.

    “For the miR-219 treatment study in mice, animal groups were randomized during treatment.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    No statistical methods were used to predetermine sample sizes for cell-based and gene expression assays and phenotypic analysis, but sample sizes are similar to those generally employed in the field.

    “For cell-based and gene expression assays as well as phenotypic analysis, no statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those generally employed in the field.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    EAE animals were scored daily while experimenters were blinded to treatment identity.

    “Animals were scored daily while experimenters were blinded to the identity of the treatments”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    miRNA-based therapeutics have an advantage over antibody therapy such as anti-Lingo1 because miRNAs are more stable.

    “miRNA-based therapeutics have an advantage over antibody therapy such as anti-Lingo1 as miRNAs are more stable (Cho, 2012; Vicente et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cho, 2012 source
    • cites Vicente et al., 2016 source

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

    Study design and conductnone given

    Littermate controls minimized differences imparted by background.

    “Littermate controls minimized any difference imparted by background.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Quantifications were performed from at least three independent experiments and quantified blindly.

    “Quantifications were performed from at least three independent experiments and quantified blindly.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    LPC-induced injuries were conducted in a genotype-blinded manner.

    “Injuries were conducted in a genotype-blinded manner.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Fluorescence images were quantified in a double-blinded manner.

    “quantified in a double-blinded manner by ImageJ”
    Quote in the paperNot a substantial claim
25 of 25

  • The paper relies on this without support.

    The molecular mechanisms that hinder oligodendrocyte regeneration and remyelination are not fully understood.

    “At present, the molecular mechanisms that hinder OL regeneration and remyelination are not fully understood.”

  • The paper relies on this without support.

    In vivo functions of miR-219 and miR-338 and their context-specific targets remain elusive.

    “however, in vivo functions of these miRNAs and their context-specific targets remain elusive.”

  • The paper relies on this without support.

    Many miRNA functions observed in vitro could not be recapitulated in vivo.

    “Given that many of the miRNA functions observed in vitro could not be recapitulated in vivo”

  • The paper relies on this without support.

    Whether miRNA mRNA targeting is stage dependent remains undetermined.

    “In addition, whether their mRNA targeting is stage dependent remains undetermined.”

  • The paper relies on this without support.

    Chronic demyelination predisposes to axonal loss in MS.

    “as chronic demyelination predisposes to axonal loss in MS”

  • The paper relies on this without support.

    Injury stimulates OPC proliferation.

    “Since injury stimulates OPC proliferation”

  • The authors state this as an assumption.

    Tests assumed a normal distribution.

    “Tests assumed a normal distribution.”
7 of 7

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?

  • In Alzheimer's disease versus controls, oligodendrocytes showed significant downregulation of genes promoting myelination through actin cytoskeleton modification, axonal guidance, and precursor differentiation.

    “A heatmap of oligodendrocyte-specific gene expression in AD versus controls revealed significant downregulation of genes that promote myelination through modification of the actin cytoskeleton, such as Stathmin 4 (STMN4)34, axonal guidance, like Semaphorin3B (SEMA3B)35, and differentiation of precursor cells into mature myelin-forming cells (MIR219A2)36”

    From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [36]

  • hsa-miR-9 was elevated in both neurons and astrocytes.

    “We found elevated levels of hsa-miR-9, a regulator of synaptic plasticity and memory 48 , both in neurons and astrocytes (Supplementary Figure 2d).”

    From Human brain microRNAs exhibit cell-type specificity and age dependence (2026) · cites this paper as [48]

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.

  • Intranasal delivery rate implies a much larger dose

    Major

    At 2 ml per minute for 20 minutes, the administered volume would be 40 ml, not the stated 14 μl. The delivery rate or duration is therefore inconsistent with the reported dose.

    Reported 14 · recomputed 40

  • Mimic-injection schedules conflict

    Major

    The results specify four consecutive days of treatment after the initial injection, but the methods say injections continued daily until tissue harvest. The paper reports evaluating tissue at dpl 8 and 14, so those schedules would differ.

  • Lingo1 antibody catalogue numbers differ

    Minor

    The resource table and staining methods give different catalogue numbers for the Millipore rabbit anti-Lingo1 antibody.

  • Lingo1 binding sites are assigned to both the coding region and UTR

    Minor

    The results place both predicted miR-219 binding sites in the Lingo1 coding region, whereas the methods identify the reporter containing the two predicted sites as a Lingo1 UTR reporter.

4 of 4

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Related

Authors
Wang, H., Moyano, A. L., Ma, Z., Deng, Y., Lin, Y., Zhao, C., Zhang, L., Jiang, M., He, X., Ma, Z., Lu, F., Xin, M., Zhou, W., Yoon, S. O., Bongarzone, E. R., & Lu, Q. R.
Affiliations
  • Cincinnati Children's Hospital Medical Center (US)
  • University of Illinois Chicago (US)
  • Children's Hospital of Fudan University (CN)
  • The Ohio State University (US)
  • Universidad de Buenos Aires (AR)
Corresponding author
Lu, Q. Richard
ORCID
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2017-03
Volume
40
Issue
6
Pages
566-582.e5
ISSN
1534-5807 (ISSN-L)
DOI
10.1016/j.devcel.2017.03.001
PMC
PMC5569304
OpenAlex
W2603769353
Cited by
174
References
57
Citations by year
2026: 13 · 2025: 17 · 2024: 20 · 2023: 15 · 2022: 17 · 2021: 27 · 2020: 19 · 2019: 29 · 2018: 11 · 2017: 6
FWCI
7.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Developmental Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (R01NS072427, R01NS075243, R01NS065808, R21NS087474)
  • National Multiple Sclerosis Society (NMSS-4727, RG 4172-A-4)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Keywords
miR-219, miR-338, microRNA, myelination, remyelination, oligodendrocyte differentiation, demyelinating disease, LINGO-1, ETV5, multiple sclerosis, experimental autoimmune encephalomyelitis, lysolecithin-induced demyelination, microRNA target regulation, oligodendrocyte precursor cells
MeSH terms
Animals, Cell Differentiation, Central Nervous System, Demyelinating Diseases, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Membrane Proteins, Mice, Inbred C57BL, Multiple Sclerosis, Myelin Sheath, Nerve Regeneration, Nerve Tissue Proteins, Oligodendroglia, Optic Nerve, Phenotype, Spinal Cord, Wound Healing, Gene Deletion, Mice, Knockout, Disease Progression, Cell Lineage, MicroRNAs, Lecithins

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