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Early emergence of cortical interneuron diversity in the mouse embryo
Open accessAbstract
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
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“This analysis revealed a prominent temporal segregation of progenitor clusters (fig. S6, B and D)”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“The profile of emerging CGE-specific interneuron classes, such as those characterized by the expression of Meis2 (21), is also delineated at this stage.”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
What the sources say
- Not checked yetcites [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
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In the paper
“This analysis revealed that regional identity segregates more clearly among E14.5 neuronal clusters (figs. S15C)”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
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In the paper
“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).”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
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In the paper
“Analysis of the expression of region- and cell type-specific genes revealed the emerging signature of the main groups of cortical interneurons (fig. S15F).”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For example, clusters primarily populated by MGE-derived cells can be further segregated into those with features of SST+ interneurons (N3 and N4) and those without (N1, N2 and N9)”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
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In the paper
“We found that developmental stage and anatomical source contribute to cell segregation (Fig. 1, B and C, and figs. S2 and S3).”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
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In the paper
“This analysis also revealed that the CGE gives rise to neurons with molecular profile of SST+ interneurons (N13)”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
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In the paper
“Many progenitor clusters found at E12.5 did not seem to have a direct transcriptional equivalent at E14.5 (fig. S10B)”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
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In the paper
“GO enrichment analysis revealed different states of maturation across neuronal clusters (fig. S15E)”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
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In the paper
“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.”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
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In the paper
“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).”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
What the sources say
- Not checked yetcites [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 yetcites [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
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Regressing out cell cycle-dependent genes removes their influence without distorting cell type identification.
In the paper
“Cross-validation using MetaNeighbor (14) confirmed cluster robustness and identity (fig. S10A).”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
What the sources say
- Not checked yetcites [14] Paul A Transcriptional architecture of synaptic communication delineates GABAergic neuron identity Cell 2017 171 522 539 e520 28942923 PMC5772785 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
What the sources say
- Not checked yetcites [20] Gelman DM Marín O Generation of interneuron diversity in the mouse cerebral cortex Eur J Neurosci 2010 31 2136 2141 20529125 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
What the sources say
- Not checked yetcites [1] Kepecs A Fishell G Interneuron cell types are fit to function Nature 2014 505 318 326 24429630 PMC4349583 source
- Not checked yetcites [9] Wamsley B Fishell G Genetic and activity-dependent mechanisms underlying interneuron diversity Nat Rev Neurosci 2017 18 299 309 28381833 source
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Transcriptional similarity between embryonic and adult neurons is sufficient to assign embryonic neurons to adult interneuron cell types.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [14] Paul A Transcriptional architecture of synaptic communication delineates GABAergic neuron identity Cell 2017 171 522 539 e520 28942923 PMC5772785 source
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The adult mouse cerebral cortex contains over 20 distinct classes of interneurons with unique transcriptional profiles (7, 8).”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
What the sources say
- Not checked yetcites [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 yetcites [8] Tasic B Adult mouse cortical cell taxonomy revealed by single cell transcriptomics Nat Neurosci 2016 19 335 346 26727548 PMC4985242 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“which suggests a difference in transcriptomic and cell-type diversity between embryo and adult.”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, core aspects of interneuron identity are drafted early in development, forming the foundation on which later interactions with other neurons must function.”
§ Early emergence of cortical interneuron diversity in the mouse embryo > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Transcriptional similarity between embryonic and adult neurons is sufficient to assign embryonic neurons to adult interneuron cell types.
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).”
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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.”
From The diversity of GABAergic neurons and neural communication elements (2019) · cites this paper as [64]
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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
MajorThe 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.
“found 6 prospective interneuron subtypes among embryonic neurons (Fig. 3A and fig. S18).”
“Comparison between the two independent approaches identified 8 conserved interneuron subtypes among the assigned embryonic neurons (Fig. 3E).”
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Metadata
- 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
- ORCID
- Venue
- Science
- Published
- 2018-04-06
- Volume
- 360
- Issue
- 6384
- Pages
- 81-85
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6195193
- OpenAlex
- W2789083734
- Semantic Scholar
- dba84bf1ab5eadff9d26cfdd75f339741258d230
- 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
- FWCI
- 13.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- 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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