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Cited by 40MicroRNA in disease regulationNeuroinflammation and Neurodegeneration MechanismsPlant Molecular Biology Research

CNS microRNA profiles: a database for cell type enriched microRNA expression across the mouse central nervous system

Open access
Pomper, Nathan, Liu, Yating, Hoye, Mariah L., Dougherty, Joseph D., Miller, Timothy M.·2020·Scientific Reports
DOI 10.1038/s41598-020-61307-5PMC PMC7080788
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Abstract

microRNAs are short, noncoding RNAs that can regulate hundreds of targets and thus shape the expression landscape of a cell. Similar to mRNA, they often exhibit cell type enriched expression and serve to reinforce cellular identity. In tissue with high cellular complexity, such as the central nervous system (CNS), it is difficult to attribute microRNA changes to a particular cell type. To facilitate interpretation of microRNA studies in these tissues, we used previously generated data to develop a publicly accessible and user-friendly database to enable exploration of cell type enriched microRNA expression. We provide illustrations of how this database can be utilized as a reference as well as for hypothesis generation. First, we suggest a putative role for miR-21 in the microglial spinal injury response. Second, we highlight data indicating that differential microRNA expression, specifically miR-326, may in part explain regional differences in inflammatory cells. Finally, we show that miR-383 expression is enriched in cortical glutamatergic neurons, suggesting a unique role in these cells. These examples illustrate the database’s utility in guiding research towards unstudied regulators in the CNS. This novel resource will aid future research into microRNA-based regulatory mechanisms responsible for cellular phenotypes within the CNS.

AI snapshot

Written from the paper’s full text.

TL;DR

The authors built a public database (miRNA.wustl.edu) of cell type–enriched microRNA expression across the mouse CNS by pooling Cre-dependent Ago2 affinity purification data from Hoye et al. 2017 and He et al. 2012. They illustrate its use by generating hypotheses for microglial miR-21 in spinal injury, regional miR-326 differences, and glutamatergic-neuron-enriched miR-383.

Key findings

  • The database provides “Search by miRNA” and “Search by cell type” functions across brainstem, spinal cord, neocortex, and cerebellum, with expression plots, differential contrasts, pSI values, and downloadable results.
  • Example 1: miR-21 is enriched in spinal microglia/immune cells, with greater expression than in spinal astrocytes, suggesting an underappreciated microglial role in the spinal injury response.
  • Example 2: miR-326-3p shows regional cell-type variability: almost exclusively microglial in brainstem, largely astrocytic in spinal cord, depleted in Purkinje neurons relative to cerebellum, and detectable in neocortical neurons, particularly interneuron subtypes.
  • Example 3: miR-383-5p is enriched in neurons over glia in brainstem and spinal cord, enriched in Purkinje neurons relative to cerebellum, and most highly expressed by CamKIIa-positive glutamatergic neurons in neocortex.
  • Table 1 reports detectable miRNAs statistically enriched relative to tissue level: e.g., brainstem motor neurons 52, spinal motor neurons 60, spinal astrocytes 63, spinal microglia 57, neocortical PV+ interneurons 115, SOM+ interneurons 152, and cerebellar Purkinje neurons 155.

Methods

  • Data were pooled from Hoye et al. 2017 and He et al. 2012, using a Cre-dependent miRNA affinity purification technique with cell type–specific GFP-tagged Ago2 followed by anti-myc capture.
  • Hoye et al. 2017 used microarray with LoessM-normalized Ct values from n = 3–4 mice per group at P63; He et al. 2012 used small RNA sequencing with counts per million from n = 2–3 animals per group at P56. All animals were C57BL/6.
  • Analyses generated relative expression, log2 fold changes, adjusted p-values for pairwise cell-type comparisons, and pSI values for enrichment versus all other cell types and total tissue. Detectability required average Ct ≤ 35 and 2 of 3 replicates above median background Ct for brainstem/spinal cord, or CPM ≥ 1 in at least two replicates for neocortex/cerebellum.
  • The website was built with Django 1.11, Python 3.6, SQLite, and mod_wsgi-express.

Limitations

  • Stated: the data were produced under physiological conditions in healthy, adult mice; the authors note it will be important to incorporate cell type–specific miRNA expression across conditions such as multiple developmental time points.
  • Stated: more comprehensive miRNA analysis of other neocortical and cerebellar cell types, and deeper brainstem/spinal cord analysis (e.g., by small RNA sequencing), would add information; the He sequencing data yielded more enriched miRNAs per cell type than the Hoye microarray data, perhaps due to greater sensitivity for less abundant miRNAs.
  • Evident from the text: the database is presently limited to the CNS, and the neocortex/cerebellum analyses lacked immunoprecipitation background data, so detectability was defined by CPM ≥ 1 in at least two replicates rather than by background Ct.

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

Integrity signals

Registry

Crossref · 10.1038/s41598-020-61307-5

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

2 of 19 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    A previous large-scale analysis of miRNA expression across 13 distinct neuroanatomical regions lacked the resolution to describe miRNA expression on a cell type specific basis within nervous system tissues.

    “Bak and colleagues undertook a large scale analysis of miRNA expression across 13 distinct neuroanatomical regions, but lacked the resolution to describe miRNA expression on a cell type specific basis within these nervous system tissues8.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Bak, M. et al. MicroRNA expression in the adult mouse central nervous system. RNA 14, 432–444 (2008). source
  • Findingown data

    miR-326 is an almost exclusively microglial miRNA within the brainstem.

    “Our database identifies miR-326 as an almost exclusively microglial miRNA within the brainstem”
    Quote in the paperSubstantial claim
  • Findingown data

    miR-383 is not equally distributed across neuronal subtypes in the neocortex.

    “the neocortical dataset reveals that miR-383 is not equally distributed across neuronal subtypes.”
    Quote in the paperSubstantial claim
  • Findingown data

    miR-383 expression is enriched in Purkinje neurons over the cerebellum as a whole.

    “miR-383 expression is similarly enriched in Purkinje neurons over the cerebellum as a whole”
    Quote in the paperNot a substantial claim
  • Findingown data

    Within the spine, miR-326 expression is largely restricted to astrocytes.

    “Within the spine, miR-326 expression is largely restricted to astrocytes (Fig. 2A).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 18
  • May combine two claims. 14

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

    Premisecitation

    miR-21 expression in astrocytes following injury both promoted glial scar formation and hindered axonal regrowth.

    “One study demonstrated miR-21 expression in astrocytes following injury both promoted glial scar formation and hindered axonal regrowth, underscoring the importance of cell types beyond neurons in the miR-21 injury response19.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Bhalala, O. G. et al. microRNA-21 Regulates Astrocytic Response Following Spinal Cord Injury. J. Neurosci. 32, 17935–17947 (2012). source

      The Introduction and Discussion report increased miR-21 in astrocytes after spinal cord injury and a role in glial-scar progression. But they do not establish that miR-21 promotes scar formation: overexpression attenuated astrocytic hypertrophy. The Results found more axons in lesions when miR-21 was inhibited, while the Discussion says it is unclear whether this reflects new growth or spared axons, so hindered axonal regrowth is overstated. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The top 10 enriched miRNAs in spinal microglia compared to all spinal neurons include miRNAs known to be associated with immune responses, such as miR-223-3p, and novel miRNAs not previously associated with microglial function.

    “Additionally, Fig. 4B highlights the top 10 enriched miRNAs in spinal microglia as compared to all spinal neurons. This analysis yields miRNAs known to be associated with immune responses, including miR-223-3p31, but also novel miRNAs that have not been previously associated with microglial function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Cantoni, C. et al. Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol. 133, 61–77 (2017). source

  • May combine two claims.

    Findingown data

    The top spinal motor neuron miRNAs relative to all other cell types assayed include both miR-218 strands and potentially novel modulators of motor neuron function, including miR-544-3p.

    “For example, Fig. 4A details the top spinal motor neuron miRNA, relative to all other cell types assayed (including pan-neuronal miRNAs). This identifies both miR-218 strands, as well as potentially novel modulators of motor neuron function, including miR-544-3p.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The database confirms expression of miR-21 in spinal astrocytes but also indicates an even greater expression in spinal microglia, consistent with brainstem expression.

    “Our database confirms the expression of miR-21 in spinal astrocytes but also indicates an even greater expression in spinal microglia, that is consistent with brainstem expression (Fig. 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    By in situ hybridization, miR-21 was expressed in neurons after injury but the majority of its expression seems to occur in other cell types.

    “By in situ hybridization, miR-21 was expressed in neurons after injury but the majority of its expression seems to occur in other cell types18.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Zhang, T. et al. The protective effect of microRNA-21 in neurons after spinal cord injury. Spinal Cord. 57, 141 (2019). source

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

    Premisecitation

    Some evidence directly points to the neurotoxic effect of microglial FasL and its repression by microglial miR-21.

    “Consistent with this, some evidence directly points to the neurotoxic effect of microglial FasL and its repression by microglial miR-2120, but this has yet to be investigated in the context of spinal cord injury.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Zhang, L., Dong, L.-Y., Li, Y.-J., Hong, Z. & Wei, W.-S. miR-21 represses FasL in microglia and protects against microglia-mediated neuronal cell death following hypoxia/ischemia. Glia 60, 1888–1895 (2012). source

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    The database adds to the existing body of resources available for studying miRNAs and broadens the information available to researchers studying miRNA regulation.

    “This database adds to the existing body of resources available for studying miRNAs, including target prediction software and broadens the wealth of information available to researchers studying miRNA regulation.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The strategy can be applied to any tissue with characterized Cre driver lines.

    “this strategy can be applied to any tissue with characterized Cre driver lines.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The miR-383 locus and target genes are associated with an increased risk for autism spectrum disorder and linked behaviors, such as rumination.

    “Further genomic-level analyses have revealed that the miR-383 locus and target genes are associated with an increased risk for autism spectrum disorder and linked behaviors, such as rumination27,28.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Eszlari, N. et al. Genome-wide association analysis reveals KCTD12 and miR-383-binding genes in the background of rumination. Transl. Psychiatry 9, 1–12 (2019). source
    • cites [28] Tabarés-Seisdedos, R. & Rubenstein, J. L. R. Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. Mol. Psychiatry 14, 563–589 (2009). source

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

    Premisenone given

    Existing miRNA tools are useful for target prediction, but fail to provide context as to whether a given miRNA and its putative target mRNA are co-expressed in the same cell type.

    “Existing miRNA tools are useful for target prediction, but fail to provide context as to whether a given miRNA and its putative target mRNA are co-expressed in the same cell type.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    miR-326 has been implicated as a pro-inflammatory miRNA in circulating CD4+ T cells.

    “miR-326 has been implicated as a pro-inflammatory miRNA in circulating CD4+ T cells21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Du, C. et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat. Immunol. 10, 1252–1259 (2009). source

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    In tissue with high cellular complexity such as the central nervous system, it is difficult to attribute microRNA changes to a particular cell type.

    “In tissue with high cellular complexity, such as the central nervous system (CNS), it is difficult to attribute microRNA changes to a particular cell type.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In response to a common peroneal nerve injury, microglia are activated within the spine, but not the medulla.

    “For example, in response to a common peroneal nerve injury, microglia are activated within the spine, but not the medulla22.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Zhang, F. et al. Selective Activation of Microglia in Spinal Cord but Not Higher Cortical Regions Following Nerve Injury in Adult Mouse. Mol. Pain. 4, 1744–8069-4–15 (2008). source

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

    Premisecitation

    miR-383 expression has been tied to several neurodevelopmental and neuropsychiatric conditions, including Rett syndrome, fragile X syndrome, bipolar disorder and schizophrenia.

    “Interestingly, the expression of miR-383 has been tied to several neurodevelopmental and neuropsychiatric conditions. This includes Rett syndrome23, fragile X syndrome24, bipolar disorder25 and schizophrenia26.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] Cheng, T.-L. et al. MeCP2 Suppresses Nuclear MicroRNA Processing and Dendritic Growth by Regulating the DGCR8/Drosha Complex. Developmental Cell 28, 547–560 (2014). source
    • cites [24] Tian, H. et al. The targeting and functions of miRNA-383 are mediated by FMRP during spermatogenesis. Cell Death Dis. 4, e617–e617 (2013). source
    • cites [25] Miller, B. H. et al. MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function. PNAS 109, 3125–3130 (2012). source

      Queued — the background check reaches it, usually within a day.

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

    Study design and conductnone given

    A miRNA was considered detectable in the brainstem and spinal cord if its average Ct ≤ 35 and if 2 of 3 biological replicates exceeded the median background Ct.

    “A miRNA was considered detectable in the brainstem and spinal cord if its average Ct ≤ 35 and if 2 of 3 biological replicates exceeded the median background Ct.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    miR-326 is expressed by more rostral neurons despite the lack of substantial neuronal expression in the brainstem, spinal cord and cerebellum.

    “This indicates further regional variability, where miR-326 is expressed by more rostral neurons despite the lack of substantial neuronal expression in the brainstem, spinal cord and cerebellum.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    miRNAs can regulate hundreds of transcripts in a given cell type.

    “Because only partial complementarity is required for a miRNA to regulate mRNA translation, miRNAs can regulate hundreds of transcripts in a given cell type4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nat. 455, 58–63 (2008). source

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Alterations in miR-383 levels and its corresponding targets may be detrimental to maintaining the proper function of neurons, particularly excitatory cortical neurons.

    “These studies suggest that alterations in miR-383 levels and its corresponding targets may be detrimental to maintaining the proper function of neurons, particularly excitatory cortical neurons.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The database is presently limited to the central nervous system.

    “While the database is presently limited to the central nervous system”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    He et al. developed a tool for genetic expression of a tagged Argonaute-2 in mice, characterizing miRNA expression in several neuronal cell types in cortex and cerebellum.

    “He et al. developed a tool for genetic expression of a tagged Argonaute-2 in mice, characterizing miRNA expression in several neuronal cell types in cortex and cerebellum9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] He, M. et al. Cell-type-based analysis of microRNA profiles in the mouse brain. Neuron 73, 35–48 (2012). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    For the neocortex and cerebellum, a miRNA was considered detectable if its CPM ≥ 1 in at least two biological replicates.

    “For the neocortex and cerebellum, where immunoprecipitation background data was not available, a miRNA was considered detectable if its CPM ≥ 1 in at least two biological replicates.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    miR-21 is significantly upregulated after spinal cord injury, causes downregulation of targets FasL and PTEN, and its expression is directly related to secondary cell death following injury.

    “Several groups have identified miR-21 as significantly upregulated after spinal cord injury, causing downregulation of targets FasL and PTEN, and its expression is directly related to secondary cell death following injury16–18.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Hu, J.-Z. et al. Anti-Apoptotic Effect of MicroRNA-21 after Contusion Spinal Cord Injury in Rats. J. Neurotrauma 30, 1349–1360 (2013). source
    • cites [17] Wang, W. et al. MicroRNA-21-5p mediates TGF-β-regulated fibrogenic activation of spinal fibroblasts and the formation of fibrotic scars after spinal cord injury. Int. J. Biol. Sci. 14, 178–188 (2018). source
    • cites [18] Zhang, T. et al. The protective effect of microRNA-21 in neurons after spinal cord injury. Spinal Cord. 57, 141 (2019). source

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

    Interpretationreasoning

    Regional differences, such as those in miR-326 expression, could underlie the differential microglial activation response.

    “Regional differences, such as those in miR-326 expression, could underlie this differential response.”
    Quote in the paperNot a substantial claim
23 of 23

  • The paper relies on this without support.

    Physiological miRNA expression profiles in healthy adult mice are informative for disease or injury states.

    “One limitation of our database is that the data were produced under physiological conditions in healthy, adult mice.”

  • The paper relies on this without support.

    Glial cells express substantially more miR-326 than neurons.

    “consistent with previous findings that glial cells express substantially more miR-326 than neurons (Fig. 2B).”

  • The paper relies on this without support.

    The two source datasets can be validly combined or compared in a single database despite platform differences.

    “The use of this sequencing technology indeed produced a greater number of enriched miRNAs per cell type in the He data over the microarray approach utilized by the Hoye data, perhaps due to the increased sensitivity to detect less abundant miRNA.”
3 of 3

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-155-5p and miR-146a-5p expression is likely driven by microglia, as both showed an over 10-fold enrichment in microglia compared to brainstem.

    “MiR-155-5p and miR-146a-5p expression is likely driven by microglia, as both showed an over 10-fold enrichment in microglia compared to brainstem38,39 (Fig. 5a, Supplementary Fig. 9a).”

    From A spatio-temporal brain miRNA expression atlas identifies sex-independent age-related microglial driven miR-155-5p increase (2025) · cites this paper as [39]

    The Results section’s Table 1 counts miRNAs enriched in brainstem microglia but does not identify miR-155-5p or miR-146a-5p or give their fold enrichment. Searches for both miRNAs and the claimed over-10-fold comparison found no passage in our copy that verifies it; the paper’s reference to a miR-155 study does not supply those measurements. (LLM, conf=0.72)

    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.

  • Hoye et al. 2017 is assigned the wrong reference number

    Minor

    The text cites Hoye et al. 2017 as reference 14, but reference 14 is Zhang et al. 2014. Hoye et al. 2017 is listed as reference 10.

1 of 1

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Authors
Pomper, N., Liu, Y., Hoye, M. L., Dougherty, J. D., & Miller, T. M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
  • Dougherty, Joseph D.
  • Miller, Timothy M.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-03-18
Volume
10
Issue
1
Pages
4921-4921
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-020-61307-5
PMC
PMC7080788
OpenAlex
W3010993893
Semantic Scholar
4ec27e6c95c2bebbc0b4d6afc7a741dabfd21133
Cited by
39
References
37
Citations by year
2026: 7 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 8 · 2021: 6 · 2020: 1
FWCI
1.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
WUSTL | Washington University School of Medicine in St. Louis (T32 GM008151)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
Keywords
microRNA expression, cell type enrichment, central nervous system, microRNA database, miR-21, microglia, spinal cord injury, miR-326, miR-383, glutamatergic neurons, cortical neurons, mice
MeSH terms
Animals, Central Nervous System, Cerebral Cortex, Gene Expression Regulation, Neurons, Organ Specificity, Spinal Cord, Gene Expression Profiling, Databases, Genetic, MicroRNAs, Mice, Transcriptome

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