Cited by 259Neurogenesis and neuroplasticity mechanismsDevelopmental Biology and Gene RegulationSingle-cell and spatial transcriptomics

Early emergence of cortical interneuron diversity in the mouse embryo

Open access
Mi, Da, Li, Zhen, Lim, Lynette, Li, Mingfeng, Moissidis, Monika, Yang, Yifei, Gao, Tianliuyun, Hu, Tim Xiaoming +4 more·2018·Science

Abstract

Embryonic hints of adult diversity: The adult brain contains dozens of different types of interneurons that control and refine neuronal circuits. Mi et al. used single-cell transcriptomics to investigate when these subtypes emerge during interneuron development in the mouse. Transcriptomes of embryonic interneurons showed similarities to adult classes of differentiated interneurons, thus dividing the immature embryonic interneurons themselves into classes. Nearly a dozen classes of embryonic neurons could be identified soon after their last mitosis by transcriptomic similarity with known classes of adult cortical interneurons. Thus, the fate of embryonic interneurons can be read in their transcriptomes well before the neurons migrate and reach their final sites of differentiation and circuit integration. Science , this issue p. 81

Integrity signals

Registry

Crossref · 10.1126/science.aar6821

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 22 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Progenitor cell clusters in the ganglionic eminences showed prominent temporal segregation.

    “This analysis revealed a prominent temporal segregation of progenitor clusters (fig. S6, B and D)”
    Quote in the paperSubstantial claim
  • Findingcitation

    The profile of emerging caudal ganglionic eminence-specific interneuron classes, such as those characterized by Meis2 expression, is delineated at this stage.

    “The profile of emerging CGE-specific interneuron classes, such as those characterized by the expression of Meis2 (21), is also delineated at this stage.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Frazer S Transcriptomic and anatomic parcellation of 5-HT3AR expressing cortical interneuron subtypes revealed by single-cell RNA sequencing Nat Commun 2017 8 14219 28134272 PMC5290279 source

      Not checked in the free run.

  • Findingown data

    Regional identity segregated more clearly among E14.5 neuronal clusters.

    “This analysis revealed that regional identity segregates more clearly among E14.5 neuronal clusters (figs. S15C)”
    Quote in the paperSubstantial claim
  • Findingown data

    Unbiased clustering of all neurons identified 13 groups of newborn neurons with distinctive gene expression profiles and unique temporal and regional identities.

    “Unbiased clustering of all neurons identified 13 groups of newborn neurons with distinctive gene expression profiles, as well as unique temporal and regional identities (figs. S15, A to D and S16).”
    Quote in the paperSubstantial claim
  • Findingown data

    Analysis of region- and cell type-specific gene expression revealed emerging signatures of the main groups of cortical interneurons.

    “Analysis of the expression of region- and cell type-specific genes revealed the emerging signature of the main groups of cortical interneurons (fig. S15F).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 2
  • May combine two claims. 10
  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    After quality control, the final single-cell dataset contained 2,003 cells and averaged about 3,200 genes per cell.

    “which following quality control (fig. S1, A to E) led to a final dataset of 2,003 cells (fig. S1F), covering on average about 3,200 genes per cell.”
    Quote in the paperNot a substantial claim
  • May combine two claims.

    Findingcitation

    The molecular diversity of ventricular zone cells was more limited than anticipated, while subventricular zone progenitors showed diversity.

    “Although the molecular diversity of VZ cells was more limited than anticipated (15, 16), this analysis revealed diversity among SVZ progenitors (Fig. 2B and figs. S11 to S14).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Flames N Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcriptional codes J Neurosci 2007 27 9682 9695 17804629 PMC4916652 source

      Not checked in the free run.

    • cites [16] Silberberg SN Subpallial Enhancer Transgenic Lines: a Data and Tool Resource to Study Transcriptional Regulation of GABAergic Cell Fate Neuron 2016 92 59 74 27710791 PMC5063253 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Radial glial cells and intermediate progenitors have distinct identities across subpallium regions, with characteristic and often complementary transcription factor expression.

    “Analysis of progenitor cell clusters confirmed that radial glial cells and intermediate progenitors have distinct identities across different regions of the subpallium, with characteristic and often complementary expression of transcription factors (e.g., Nkx2-1 and Pax6 in VZ, Lhx6 and Foxp2 in SVZ) (Fig. 2B and figs. S11 and S12).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Findingown data

    Ventricular zone and subventricular zone progenitor clusters were distinguished at both E12.5 and E14.5 independently of cell cycle state, and they had unique gene expression patterns.

    “We then carried out semi-supervised clustering and distinguished VZ and SVZ progenitor clusters at both developmental stages (Fig. 2A and fig. S7B), independent of their cell cycle state (fig. S8), and found unique patterns of gene expression (figs. S9).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Regressing out cell cycle-dependent genes removes their influence without distorting cell type identification.
  • May combine two claims.

    Study design and conductown data

    MetaNeighbor cross-validation confirmed the robustness and identity of progenitor clusters.

    “Cross-validation using MetaNeighbor (14) confirmed cluster robustness and identity (fig. S10A).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Paul A Transcriptional architecture of synaptic communication delineates GABAergic neuron identity Cell 2017 171 522 539 e520 28942923 PMC5772785 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most parvalbumin-expressing and somatostatin-expressing interneurons are born in the medial ganglionic eminence, whereas the caudal ganglionic eminence is the origin of vasoactive intestinal peptide-expressing interneurons and neurogliaform cells.

    “Most parvalbumin (PV)-expressing and somatostatin (SST)-expressing interneurons are born in the MGE, whereas the CGE is the origin of vasoactive intestinal peptide (VIP)-expressing interneurons and neurogliaform (NDNF+) cells (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Gelman DM Marín O Generation of interneuron diversity in the mouse cerebral cortex Eur J Neurosci 2010 31 2136 2141 20529125 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Interneuron diversity does not emerge in response to activity-dependent mechanisms in the cortex, but is established early before cells reach the cortex by specific transcriptional programs that unfold over weeks.

    “This suggests that interneuron diversity does not emerge in response to activity-dependent mechanisms in the cortex (1, 9), but rather is established early, before these cells reach the cortex, by specific transcriptional programs that then unfold over the course of several weeks.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Kepecs A Fishell G Interneuron cell types are fit to function Nature 2014 505 318 326 24429630 PMC4349583 source

      Not checked in the free run.

    • cites [9] Wamsley B Fishell G Genetic and activity-dependent mechanisms underlying interneuron diversity Nat Rev Neurosci 2017 18 299 309 28381833 source

      Not checked in the free run.

    • Rests on an assumption: Transcriptional similarity between embryonic and adult neurons is sufficient to assign embryonic neurons to adult interneuron cell types.
  • May combine two claims.

    Interpretationcitation

    Activity-dependent mechanisms influence development, maturation and plasticity of cortical interneurons, but most aspects directly linked to functional diversity seem intrinsically determined.

    “Activity-dependent mechanisms undoubtedly influence development, maturation and plasticity of cortical interneurons (24–26), but most aspects that are directly linked to the functional diversity of cortical interneurons seem to be intrinsically determined (14, 27).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [24] Bortone D Polleux F KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner Neuron 2009 62 53 71 19376067 PMC3314167 source

      Not checked in the free run.

    • cites [25] De Marco Garcia NV Karayannis T Fishell G Neuronal activity is required for the development of specific cortical interneuron subtypes Nature 2011 472 351 355 21460837 PMC3641515 source

      Not checked in the free run.

    • cites [26] Dehorter N Tuning of fast-spiking interneuron properties by an activity-dependent transcriptional switch Science 2015 349 1216 1220 26359400 PMC4702376 source

      Not checked in the free run.

    • cites [14] Paul A Transcriptional architecture of synaptic communication delineates GABAergic neuron identity Cell 2017 171 522 539 e520 28942923 PMC5772785 source

      Not checked in the free run.

    • cites [27] Bartolini G Ciceri G Marín O Integration of GABAergic interneurons into cortical cell assemblies: lessons from embryos and adults Neuron 2013 79 849 864 24012001 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The adult mouse cerebral cortex contains over 20 distinct classes of interneurons with unique transcriptional profiles.

    “The adult mouse cerebral cortex contains over 20 distinct classes of interneurons with unique transcriptional profiles (7, 8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Zeisel A Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq Science 2015 347 1138 1142 25700174 source

      Not checked in the free run.

    • cites [8] Tasic B Adult mouse cortical cell taxonomy revealed by single cell transcriptomics Nat Neurosci 2016 19 335 346 26727548 PMC4985242 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    There is a difference in transcriptomic and cell-type diversity between embryo and adult.

    “which suggests a difference in transcriptomic and cell-type diversity between embryo and adult.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Interpretationreasoning

    Core aspects of interneuron identity are drafted early in development, forming the foundation on which later interactions with other neurons must function.

    “Thus, core aspects of interneuron identity are drafted early in development, forming the foundation on which later interactions with other neurons must function.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Transcriptional similarity between embryonic and adult neurons is sufficient to assign embryonic neurons to adult interneuron cell types.
11 of 11
  • The paper relies on this without support.

    Transcriptional similarity between embryonic and adult neurons is sufficient to assign embryonic neurons to adult interneuron cell types.

    “We then assigned prospective identities to embryonic neurons based on transcriptional similarity with adult interneurons.”
    “We then used the identified adult interneuron cell types to annotate the embryonic dataset using the RF classification workflow”
  • The paper relies on this without support.

    Changes in the relative proportion or density of SST+ and PV+ interneurons after Maf manipulation reflect altered fate specification rather than differences in survival, proliferation, or migration.

    “We found that widespread expression of Maf in MGE progenitors increases the relative proportion of SST+ interneurons at the expense of PV+ cells (Fig. 4F and fig. S24C).”
    “Conversely, conditional loss of Maf from MGE progenitor cells decreases the density of cortical SST+ interneurons (Fig. 4, G and H).”
  • The paper relies on this without support.

    Regressing out cell cycle-dependent genes removes their influence without distorting cell type identification.

    “We performed regression analysis on these cells to remove the influence of cell cycle-dependent genes in cell type identification (fig. S1G).”
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?

  • GABAergic interneurons born in the ganglionic eminences migrate tangentially to the proper place within prefrontal subdomains.

    “Born in the ganglionic eminences, GABAergic interneurons migrate tangentially to the proper place within the prefrontal subdomains [66, 67].”

    From Development of prefrontal cortex (2022) · cites this paper as [67]

    The Abstract (page unavailable) identifies the ganglionic eminences as the origin of cortical GABAergic interneurons and says these cells reach a final position in the cerebral cortex. It does not establish tangential migration or specify destinations within prefrontal subdomains. (LLM, conf=0.86)

    Experimental — accuracy not yet measured
  • The cardinal identity of a cell is probably already instilled at the postmitotic stage during development, and its subsequent phenotypic differentiation and expression are regulated by extrinsic signals such as cell interactions and neural activity.

    “The cardinal identity of a cell is probably already instilled at the postmitotic stage during development9,61,62,63,64, and its subsequent phenotypic differentiation and expression are regulated by extrinsic signals such as cell interactions and neural activity.”

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.

  • Overlap of eight subtypes exceeds the six found by one method

    Major

    The RF approach identified six prospective embryonic subtypes. An overlap between the RF and CCA approaches cannot contain eight subtypes if the RF approach identified only six.

1 of 1

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Authors
Mi, D., Li, Z., Lim, L., Li, M., Moissidis, M., Yang, Y., Gao, T., Hu, T. X., Pratt, T., Price, D. J., Sestan, N., & Marín, O.
Affiliations
  • King's College London (GB)
  • Yale University (US)
  • University of Edinburgh (GB)
  • Harvard University (US)
  • Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
  • Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London SE1 1UL, UK.
Corresponding author
  • Mi, Da
  • Li, Zhen
Venue
Science
Published
2018-04-06
Volume
360
Issue
6384
Pages
81-85
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2789083734
Cited by
259
References
45
Citations by year
2026: 14 · 2025: 18 · 2024: 21 · 2023: 32 · 2022: 30 · 2021: 41 · 2020: 39 · 2019: 37 · 2018: 26 · 2017: 1
FWCI
13.14
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders
  • Wellcome Trust (103714MA)
  • Medical Research Council (N012291)
  • Biotechnology and Biological Sciences Research Council (N006542)
  • National Institute for Health (NS095654, MH106934)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
cortical interneurons, GABAergic neurons, interneuron diversity, ganglionic eminence, neural progenitor cells, cortical development, transcriptional programs, single-cell transcriptomics, mouse embryo, postmitotic neurons, neuronal differentiation
MeSH terms
Animals, Cerebral Cortex, Embryo, Mammalian, Female, Interneurons, Male, Mice, Inbred Strains, Mitosis, Transcription, Genetic, Gene Expression Profiling, Mice, Neurogenesis, Neural Stem Cells, Single-Cell Analysis, GABAergic Neurons, Transcriptome

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