CoChat
Sign Up
Cited by 427Neurogenesis and neuroplasticity mechanismsSingle-cell and spatial transcriptomicsDevelopmental Biology and Gene Regulation

Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia

Open access
Eze, Ugomma C., Bhaduri, Aparna, Haeussler, Maximilian, Nowakowski, Tomasz J., Kriegstein, Arnold R.·2021·Nature Neuroscience
DOI 10.1038/s41593-020-00794-1PMC PMC8012207

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

The human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41593-020-00794-1

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Radial glia share transcriptomic similarities with mature astrocytes and are progenitor cells that give rise to numerous distinct cell fates, including neuronal cells, astrocytes, oligodendrocytes, and ependymal cells.

    “Radial glia, which share transcriptomic similarities with mature astrocytes, are progenitor cells that give rise to numerous distinct cell fates, including neuronal cells, astrocytes, oligodendrocytes, and ependymal cells.34,35”

    From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [35]

    The Results (RNA-Velocity Analysis of Lineage; page unavailable) describe radial glia giving rise to neurons, and the Discussion (page unavailable) describes progenitors giving rise to neuronal and glial diversity. Our copy does not establish transcriptomic similarity between radial glia and mature astrocytes or identify astrocytes, oligodendrocytes, and ependymal cells as the specific fates claimed. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 45

  1. [1]Breunig JJ, Haydar TF & Rakic P Neural stem cells: historical perspective and future prospects. Neuron 70, 614– 625, doi: 10.1016/j.neuron.2011.05.005 (2011). 21609820 PMC3225274 · DOI
  2. [2]Wilson SW & Houart C Early steps in the development of the forebrain. Dev Cell 6, 167– 181, doi: 10.1016/s1534-5807(04)00027-9 (2004). 14960272 PMC2789258 · DOI
  3. [3]Beccari L, Marco-Ferreres R & Bovolenta P The logic of gene regulatory networks in early vertebrate forebrain patterning. Mech Dev 130, 95– 111, doi: 10.1016/j.mod.2012.10.004 (2013). 23111324 · DOI
  4. [4]Lui JH, Hansen DV & Kriegstein AR Development and evolution of the human neocortex. Cell 146, 18– 36, doi: 10.1016/j.cell.2011.06.030 (2011). 21729779 PMC3610574 · DOI · Paper page
  5. [5]Gotz M, Hartfuss E & Malatesta P Radial glial cells as neuronal precursors: a new perspective on the correlation of morphology and lineage restriction in the developing cerebral cortex of mice. Brain Res Bull 57, 777– 788, doi: 10.1016/s0361-9230(01)00777-8 (2002). 12031274 · DOI
  6. [6]Miller FD & Gauthier AS Timing is everything: making neurons versus glia in the developing cortex. Neuron 54, 357– 369, doi: 10.1016/j.neuron.2007.04.019 (2007). 17481390 · DOI · Paper page
  7. [7]Bhaduri A Cell stress in cortical organoids impairs molecular subtype specification. Nature 578, 142– 148, doi: 10.1038/s41586-020-1962-0 (2020). 31996853 PMC7433012 · DOI · Paper page
  8. [8]Cardoso-Moreira M Gene expression across mammalian organ development. Nature 571, 505– 509, doi: 10.1038/s41586-019-1338-5 (2019). 31243369 PMC6658352 · DOI · Paper page
  9. [9]Tumpel S, Wiedemann LM & Krumlauf R Hox genes and segmentation of the vertebrate hindbrain. Curr Top Dev Biol 88, 103– 137, doi: 10.1016/S0070-2153(09)88004-6 (2009). 19651303 · DOI · Paper page
  10. [10]Agoston Z, Li N, Haslinger A, Wizenmann A & Schulte D Genetic and physical interaction of Meis2, Pax3 and Pax7 during dorsal midbrain development. BMC Dev Biol 12, 10, doi: 10.1186/1471-213X-12-10 (2012). 22390724 PMC3313853 · DOI
  11. [11]Chen L, Guo Q & Li JY Transcription factor Gbx2 acts cell-nonautonomously to regulate the formation of lineage-restriction boundaries of the thalamus. Development 136, 1317– 1326, doi: 10.1242/dev.030510 (2009). 19279136 PMC2687463 · DOI
  12. [12]Du T, Xu Q, Ocbina PJ & Anderson SA NKX2.1 specifies cortical interneuron fate by activating Lhx6. Development 135, 1559– 1567, doi: 10.1242/dev.015123 (2008). 18339674 · DOI
  13. [13]Tao W & Lai E Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork head gene family, in the developing rat brain. Neuron 8, 957– 966, doi: 10.1016/0896-6273(92)90210-5 (1992). 1350202 · DOI
  14. [14]Molyneaux BJ, Arlotta P, Hirata T, Hibi M & Macklis JD Fezl is required for the birth and specification of corticospinal motor neurons. Neuron 47, 817– 831, doi: 10.1016/j.neuron.2005.08.030 (2005). 16157277 · DOI
  15. [15]Nowakowski TJ Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex. Science 358, 1318– 1323, doi: 10.1126/science.aap8809 (2017). 29217575 PMC5991609 · DOI · Paper page
  16. [16]Alzu’bi A, Homman-Ludiye J, Bourne JA & Clowry GJ Thalamocortical Afferents Innervate the Cortical Subplate much Earlier in Development in Primate than in Rodent. Cerebral cortex 29, 1706– 1718, doi: 10.1093/cercor/bhy327 (2019). 30668846 PMC6418397 · DOI
  17. [17]Cardenas A Evolution of Cortical Neurogenesis in Amniotes Controlled by Robo Signaling Levels. Cell 174, 590– 606 e521, doi: 10.1016/j.cell.2018.06.007 (2018). 29961574 PMC6063992 · DOI
  18. [18]Li CM, Yan RT & Wang SZ Misexpression of a bHLH gene, cNSCL1, results in abnormal brain development. Dev Dyn 215, 238– 247, doi: 10.1002/(SICI)1097-0177(199907)215:3<238::AID-AJA6>3.0.CO;2-F (1999). 10398534 PMC1764459 · DOI
  19. [19]Conde F, Lund JS, Jacobowitz DM, Baimbridge KG & Lewis DA Local circuit neurons immunoreactive for calretinin, calbindin D-28k or parvalbumin in monkey prefrontal cortex: distribution and morphology. J Comp Neurol 341, 95– 116, doi: 10.1002/cne.903410109 (1994). 8006226 · DOI
  20. [20]Li H Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proceedings of the National Academy of Sciences of the United States of America 105, 9397– 9402, doi: 10.1073/pnas.0802876105 (2008). 18599437 PMC2453715 · DOI
  21. [21]Harrington AJ MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. Elife 5, doi: 10.7554/eLife.20059 (2016). PMC5094851 27779093 · DOI · Paper page
  22. [23]Miquelajauregui A LIM-homeobox gene Lhx5 is required for normal development of Cajal-Retzius cells. The Journal of neuroscience: the official journal of the Society for Neuroscience 30, 10551– 10562, doi: 10.1523/JNEUROSCI.5563-09.2010 (2010). 20685998 PMC2927820 · DOI
  23. [24]Manuel MN The transcription factor Foxg1 regulates telencephalic progenitor proliferation cell autonomously, in part by controlling Pax6 expression levels. Neural Dev 6, 9, doi: 10.1186/1749-8104-6-9 (2011). 21418559 PMC3068069 · DOI
  24. [26]Subramanian L, Bershteyn M, Paredes MF & Kriegstein AR Dynamic behaviour of human neuroepithelial cells in the developing forebrain. Nature communications 8, 14167, doi: 10.1038/ncomms14167 (2017). PMC5290330 28139695 · DOI
  25. [27]Qin J Early Forebrain Neurons and Scaffold Fibers in Human Embryos. Cerebral cortex 30, 913– 928, doi: 10.1093/cercor/bhz136 (2020). 31298263 · DOI
  26. [29]Virgintino D Astroglia-microvessel relationship in the developing human telencephalon. Int J Dev Biol 42, 1165– 1168 (1998). 9879715
  27. [30]Aaku-Saraste E, Hellwig A & Huttner WB Loss of occludin and functional tight junctions, but not ZO-1, during neural tube closure--remodeling of the neuroepithelium prior to neurogenesis. Developmental biology 180, 664– 679, doi: 10.1006/dbio.1996.0336 (1996). 8954735 · DOI
  28. [31]Hatakeyama J Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131, 5539– 5550, doi: 10.1242/dev.01436 (2004). 15496443 · DOI
  29. [32]Sahara S & O’Leary DD Fgf10 regulates transition period of cortical stem cell differentiation to radial glia controlling generation of neurons and basal progenitors. Neuron 63, 48– 62, doi: 10.1016/j.neuron.2009.06.006 (2009). 19607792 PMC2746711 · DOI
  30. [34]Qian X, Riccio A, Zhang Y & Ginty DD Identification and characterization of novel substrates of Trk receptors in developing neurons. Neuron 21, 1017– 1029, doi: 10.1016/s0896-6273(00)80620-0 (1998). 9856458 · DOI
  31. [35]Tessarollo L trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues. Development 118, 463– 475 (1993). 8223273
  32. [36]Pellegrini L Human CNS barrier-forming organoids with cerebrospinal fluid production. Science, doi: 10.1126/science.aaz5626 (2020). PMC7116154 32527923 · DOI
  33. [37]Bray SJ, Takada S, Harrison E, Shen SC & Ferguson-Smith AC The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila. BMC Dev Biol 8, 11, doi: 10.1186/1471-213X-8-11 (2008). 18237417 PMC2268666 · DOI
  34. [38]Miller AJ & Cole SE Multiple Dlk1 splice variants are expressed during early mouse embryogenesis. Int J Dev Biol 58, 65– 70, doi: 10.1387/ijdb.130316sc (2014). 24860997 · DOI
  35. [39]Ferron SR Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature 475, 381– 385, doi: 10.1038/nature10229 (2011). 21776083 PMC3160481 · DOI
  36. [40]Chakravarti S Functions of lumican and fibromodulin: lessons from knockout mice. Glycoconj J 19, 287– 293, doi: 10.1023/A:1025348417078 (2002). 12975607 · DOI
  37. [41]Long KR Extracellular Matrix Components HAPLN1, Lumican, and Collagen I Cause Hyaluronic Acid-Dependent Folding of the Developing Human Neocortex. Neuron 99, 702– 719 e706, doi: 10.1016/j.neuron.2018.07.013 (2018). 30078576 · DOI · Paper page
  38. [42]Zhao Q, Behringer RR & de Crombrugghe B Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene. Nat Genet 13, 275– 283, doi: 10.1038/ng0796-275 (1996). 8673125 · DOI
  39. [43]Gaiano N, Nye JS & Fishell G Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron 26, 395– 404, doi: 10.1016/s0896-6273(00)81172-1 (2000). 10839358 · DOI
  40. [44]Endo M, Antonyak MA & Cerione RA Cdc42-mTOR signaling pathway controls Hes5 and Pax6 expression in retinoic acid-dependent neural differentiation. The Journal of biological chemistry 284, 5107– 5118, doi: 10.1074/jbc.M807745200 (2009). 19097998 PMC3837441 · DOI
  41. [45]Harrison-Uy SJ & Pleasure SJ Wnt signaling and forebrain development. Cold Spring Harb Perspect Biol 4, a008094, doi: 10.1101/cshperspect.a008094 (2012). 22621768 PMC3385962 · DOI
  42. [47]Yuzwa SA Developmental Emergence of Adult Neural Stem Cells as Revealed by Single-Cell Transcriptional Profiling. Cell reports 21, 3970– 3986, doi: 10.1016/j.celrep.2017.12.017 (2017). 29281841 · DOI
  43. [48]Jeffrey PL CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types. Molecular and cellular neurosciences 16, 185– 196, doi: 10.1006/mcne.2000.0866 (2000). 10995546 · DOI
  44. [49]Bedford L Id4 is required for the correct timing of neural differentiation. Developmental biology 280, 386– 395, doi: 10.1016/j.ydbio.2005.02.001 (2005). 15882580 · DOI
  45. [50]Choe Y, Zarbalis KS & Pleasure SJ Neural crest-derived mesenchymal cells require Wnt signaling for their development and drive invagination of the telencephalic midline. PloS one 9, e86025, doi: 10.1371/journal.pone.0086025 (2014). 24516524 PMC3916303 · DOI

Cited by

Sorted by citations

Authors
Eze, U. C., Bhaduri, A., Haeussler, M., Nowakowski, T. J., & Kriegstein, A. R.
Affiliations
  • University of California, San Francisco (US)
  • University of California, Santa Cruz (US)
Corresponding author
  • Bhaduri, Aparna
  • Kriegstein, Arnold R.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2021-03-15
Volume
24
Issue
4
Pages
584-594
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-020-00794-1
PMC
PMC8012207
OpenAlex
W3137406645
Cited by
427
References
5
Citations by year
2026: 44 · 2025: 81 · 2024: 94 · 2023: 111 · 2022: 71 · 2021: 24 · 2020: 2
FWCI
28.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (U01MH114825, F32NS103266, K99NS111731)
  • American Association for the Advancement of Science (For Women in Science Fellowship)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
human brain development, neuroepithelial cells, telencephalon, diencephalon, midbrain, hindbrain, cerebellum, organoid models, neurogenesis, single-cell atlas
MeSH terms
Animals, Cerebral Cortex, Humans, Neuroepithelial Cells, Neurogenesis, Neural Stem Cells, Single-Cell Analysis, Ependymoglial Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review