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

Trygve E. Bakken*, Nikolas L. Jorstad, Qiwen Hu, Wei Tian, Brian E. Kalmbach, Jeroen Eggermont, Brian D. Aevermann, Thomas Höllt, Boudewijn P. Lelieveldt, More Authors

*Corresponding author for this work

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The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. 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.

Original languageEnglish
Pages (from-to)111-119
Number of pages9
Issue number7879
Publication statusPublished - 2021

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Author Correction: Comparative cellular analysis of motor cortex in human, marmoset and mouse
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Published: 22 March 2022

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

Trygve E. Bakken, Nikolas L. Jorstad, …Ed S. Lein

Nature (2022)Cite this article

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The Original Article was published on 06 October 2021

Correction to: Nature Published online 6 October 2021

In the version of this article initially published, the Acknowledgements section was incomplete and has now been amended to include the following: “NIH BRAIN Initiative awards U01 MH121282 to J.R.E and M.M.B, U19 MH114831 to J.R.E. and E.M.C., U19 MH114830 to H.Z., U01 MH114819 to G.F., 1U01MH114828 to K.Z. and J.C., RF1MH123220 to M.H. and R.H.S., and U19 MH114821. NIH awards R01DC019370 to R.H., R24MH114815 to R.H. and O.R.W., and R24 MH114788 to O.R.W. Nancy and Buster Alvord Endowment to C.D.K.” The changes have been made to the HTML and PDF versions of the article


Acknowledgements We thank the tissue procurement, tissue processing and facilities teams at the Allen Institute for Brain Science for assistance with the transport and processing of postmortem and neurosurgical brain specimens; the technology team at the Allen Institute for assistance with data management; M. Vawter, J. Davis and the San Diego Medical Examiner’s Office for assistance with postmortem tissue donations; X. Opitz-Araya and the Allen Institute for Brain Science viral technology team for AAV packaging; K. Brouner, A. Ruiz, T. Egdorf, A. Gary, M. Maxwell, A. Pom and J. Bomben for biocytin staining; N. Dotson, R. Enstrom, M. Hupp, L. Potekhina and S. Ransford for imaging biocytin-filled cells; L. Ng, D. Hill and R. Rajanbabu for patching the human and mouse cells in Figure 5 describing chandelier neurons; and S. Kebede, A. Mukora and G. Willams for reconstructing these cells. This work was funded by the Allen Institute for Brain Science and by US National Institutes of Health (NIH) grant U01 MH114812-02 to E.S.L. Support for the development of NS-Forest v.2 and the provisional cell ontology was provided by the Chan–Zuckerberg Initiative Donor-Advised Fund (DAF), an advised fund of the Silicon Valley Community Foundation (2018-182730). G.Q. is supported by National Science Foundation (NSF) CAREER award 1846559. S.O. is supported by the NARSAD Young Investigator Award. This work was partially supported by a Dutch Research Council (NWO) Gravitation project, BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO grant 024.004.012) and NWO TTW project 3DOMICS (NWO grant 17126). This project was supported in part by NIH grants P51OD010425 from the Office of Research Infrastructure Programs (ORIP) and UL1TR000423 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH, ORIP, NCATS, the Institute of Translational Health Sciences or the University of Washington National Primate Research Center. This work is supported in part by NIH BRAIN Initiative award RF1MH114126 from the National Institute of Mental Health to E.S.L., J.T.T. and B.P.L.; NIH BRAIN Initiative award U19MH121282 to J.R.E.; National Institute on Drug Abuse award R01DA036909 to B.T.; National Institute of Neurological Disorders and Stroke award R01NS044163 to W.J.S.; and the California Institute for Regenerative Medicine (GC1R-06673-B) and the Chan–Zuckerberg Initiative DAF, an advised fund of the Silicon Valley Community Foundation (2018–182730), to R.H.S. J.R.E. is an Investigator of the Howard Hughes Medical Institute. The authors thank the founder of the Allen Institute, Paul G. Allen, for his vision, encouragement and support.


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