Cited by 812Single-cell and spatial transcriptomicsNeuroscience and Neuropharmacology ResearchGenomics and Chromatin Dynamics

Comparative cellular analysis of motor cortex in human, marmoset and mouse

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Bakken, Trygve E., Jorstad, Nikolas L., Hu, Qiwen, Lake, Blue B., Tian, Wei, Kalmbach, Brian E., Crow, Megan, Hodge, Rebecca D. +98 more·2021·Nature

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Abstract

. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

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  • Human single nucleus RNA sequencing data from Bakken and colleagues were obtained from the Human Protein Atlas.

    “Human single nucleus RNA sequencing data from Bakken and colleagues [11] were obtained from the Human Protein Atlas (proteinatlas.org).”
  • Apart from PSEN2, oligodendrocytes had elevated expression of all genes involved in amyloid beta production in human single-nucleus RNA sequencing datasets.

    “We found that, apart from PSEN2 (which is not essential for gamma secretase function when PSEN1 is present [13]), oligodendrocytes had elevated expression of all of these genes (Fig 1A–1D).”

    From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [11]

    The citation is attached to the parenthetical claim that PSEN2 is not essential for gamma-secretase function when PSEN1 is present. Our copy’s Methods > SNARE–seq2 and Consensus M1 taxonomy across species passages discuss oligodendrocyte profiling, but do not address PSEN1, PSEN2, gamma-secretase function, or elevated expression of amyloid-beta-production genes. Searches for those terms found no decisive passage. (LLM, conf=0.75)

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  1. [15]Evarts, E. V. in Neurophysiological Basis of Normal and Abnormal Motor Activities 215–253 (Raven Press, New York, 1967).
  2. [57]Wickham, H. ggplot2: Elegant Graphics for Data Analysis (Springer, 2016).

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Authors
Bakken, T. E., Jorstad, N. L., Hu, Q., Lake, B. B., Tian, W., Kalmbach, B. E., Crow, M., Hodge, R. D., Krienen, F. M., Sorensen, S. A., Eggermont, J., Yao, Z., Aevermann, B. D., Aldridge, A. I., Bartlett, A., Bertagnolli, D., Casper, T., Castanon, R. G., Crichton, K., Daigle, T. L., Dalley, R., Dee, N., Dembrow, N., Diep, D., Ding, S.-L., Dong, W., Fang, R., Fischer, S., Goldman, M., Goldy, J., Graybuck, L. T., Herb, B. R., Hou, X., Kancherla, J., Kroll, M., Lathia, K., van Lew, B., Li, Y. E., Liu, C. S., Liu, H., Lucero, J. D., Mahurkar, A., McMillen, D., Miller, J. A., Moussa, M., Nery, J. R., Nicovich, P. R., Niu, S.-Y., Orvis, J., Osteen, J. K., Owen, S., Palmer, C. R., Pham, T., Plongthongkum, N., Poirion, O., Reed, N. M., Rimorin, C., Rivkin, A., Romanow, W. J., Sedeño-Cortés, A. E., Siletti, K., Somasundaram, S., Sulc, J., Tieu, M., Torkelson, A., Tung, H., Wang, X., Xie, F., Yanny, A. M., Zhang, R., Ament, S. A., Behrens, M. M., Bravo, H. C., Chun, J., Dobin, A., Gillis, J., Hertzano, R., Hof, P. R., Höllt, T., Horwitz, G. D., Keene, C. D., Kharchenko, P. V., Ko, A. L., Lelieveldt, B. P., Luo, C., Mukamel, E. A., Pinto-Duarte, A., Preissl, S., Regev, A., Ren, B., Scheuermann, R. H., Smith, K., Spain, W. J., White, O. R., Koch, C., Hawrylycz, M., Tasic, B., Macosko, E. Z., McCarroll, S. A., Ting, J. T., Zeng, H., Zhang, K., Feng, G., Ecker, J. R., Linnarsson, S., & Lein, E. S.
Affiliations
  • Allen Institute for Brain Science (US)
  • Harvard University (US)
  • University of California San Diego (US)
  • Salk Institute for Biological Studies (US)
  • Cold Spring Harbor Laboratory (US)
  • Leiden University Medical Center (NL)
  • J. Craig Venter Institute (US)
  • University of Washington (US)
  • University of Maryland, Baltimore (US)
  • University of Maryland, College Park (US)
  • Sanford Burnham Prebys Medical Discovery Institute (US)
  • University of Connecticut (US)
  • Karolinska Institutet (SE)
  • Washington University in St. Louis (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Delft University of Technology (NL)
  • University of California, Los Angeles (US)
  • Broad Institute (US)
Corresponding author
  • Bakken, Trygve E.
  • Lein, Ed S.
ORCID
Venue
Nature
Published
2021-10-06
Volume
598
Issue
7879
Pages
111-119
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W3204443805
Cited by
812
References
122
Citations by year
2026: 134 · 2025: 159 · 2024: 157 · 2023: 180 · 2022: 114 · 2021: 50 · 2020: 17 · 2018: 1
FWCI
40.67
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Repository (Delft University of Technology) (publishedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Science Foundation (CAREER, 1846559)
  • Howard Hughes Medical Institute
  • California Institute for Regenerative Medicine (GC1R-06673, GC1R-06673-B)
  • Silicon Valley Community Foundation (2018-182730)
  • Nancy and Buster Alvord Endowment
  • University of Washington (UL1 TR000423)
  • National Alliance for Research on Schizophrenia and Depression
  • Institute of Translational Health Sciences (UL1 TR000423)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (024.004.012, 17126)
  • National Institutes of Health (5u01mh114812-03, UL1TR000423, 1rf1mh123220-01, U01 MH114812-02, MH114812-02, MH114821, P51OD010425)
  • National Institute on Aging (P30AG066509)
  • National Institute of Mental Health (U01MH114828, U19MH114821, U01 MH114812-02, U19MH114831, RF1 MH123220, U01MH114812, U01MH114819, RF1MH114126, U01MH121282, R24MH114815, U19MH114830, MH114821, R24MH114788, MH114831)
  • National Institute on Drug Abuse (R01DA036909)
  • National Human Genome Research Institute (R01HG009318)
  • National Institute on Deafness and Other Communication Disorders (R01DC019370, U01DC013817)
  • National Institute of Neurological Disorders and Stroke (R01NS044163)
  • National Center for Advancing Translational Sciences
  • Office of Research Infrastructure Programs, National Institutes of Health (P51OD010425)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
motor cortex, single-nucleus transcriptomics, DNA methylation, chromatin state, layer 5, Patch-seq, marmoset, non-human primates, mice, cell type markers, species-specific adaptation
MeSH terms
Animals, Atlases as Topic, Callithrix, Female, Glutamates, Humans, Male, Middle Aged, Motor Cortex, Neurons, Organ Specificity, Phylogeny, Species Specificity, In Situ Hybridization, Fluorescence, Gene Expression Profiling, Epigenesis, Genetic, Mice, Epigenomics, Single-Cell Analysis, GABAergic Neurons, Transcriptome

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