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Published October 2023 | Published
Journal Article Open

A lamprey neural cell type atlas illuminates the origins of the vertebrate brain


The vertebrate brain emerged more than ~500 million years ago in common evolutionary ancestors. To systematically trace its cellular and molecular origins, we established a spatially resolved cell type atlas of the entire brain of the sea lamprey—a jawless species whose phylogenetic position affords the reconstruction of ancestral vertebrate traits—based on extensive single-cell RNA-seq and in situ sequencing data. Comparisons of this atlas to neural data from the mouse and other jawed vertebrates unveiled various shared features that enabled the reconstruction of cell types, tissue structures and gene expression programs of the ancestral vertebrate brain. However, our analyses also revealed key tissues and cell types that arose later in evolution. For example, the ancestral brain was probably devoid of cerebellar cell types and oligodendrocytes (myelinating cells); our data suggest that the latter emerged from astrocyte-like evolutionary precursors in the jawed vertebrate lineage. Altogether, our work illuminates the cellular and molecular architecture of the ancestral vertebrate brain and provides a foundation for exploring its diversification during evolution.

Copyright and License

© The Author(s) 2023, corrected publication 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.


We thank all members of the Kaessmann group for fruitful discussions; Robert Frömel for his help with library sequencing; E. Panzariello, M. Sanchez-Delgado and N. Trost for the brain and animal illustrations; M. Mall for providing temporary lab space; and M. Cardoso-Moreira for discussions and comments on the manuscript. The computations were performed on the Kaessmann lab server (managed by N. Trost) and the bwForCluster from the Heidelberg University Computational Center (supported by the state of Baden-Württemberg through bwHPC and the German Research Foundation, INST 35/1134-1 FUGG). We thank W. Wang of the Northwestern Polytechnical University of Xi'an, China; Y. Zhang of the Institute of Zoology, Chinese Academy of Sciences; and J. Pascual-Anaya from the University of Málaga, Spain, for granting access to the early draft of the inshore hagfish genome (https://doi.org/10.1101/2023.04.08.536076). This work was supported by grants from the European Research Council (no. 615253, OntoTransEvol), the European Commission (Marie Skłodowska-Curie Actions ITN: EvoCELL) and the Tschira foundation, which funded the Illumina NextSeq machine used for sequencing. D.M.M. and D.J. were supported by grants from the National Science Foundation (IOS 1656843), the National Institutes of Health/National Institute of Dental and Craniofacial Research (RDE025940) and University of Colorado, Boulder RIO Innovative Seed Grant FY21 (all to D.M.M.). D.J. was also supported by a grant from the Scientific Grant Agency of the Slovak Republic (VEGA 1/0450/21). This project has received funding from the European Research Council under the European Union's Horizon 2020 research and innovation programme (VerteBrain to H.K., grant agreement no. 101019268; and NeuralCellTypeEvo to D.A., grant agreement no. 788921).


These authors contributed equally: Francesco Lamanna, Francisca Hervas-Sotomayor.

F.L., F.H.-S. and H.K. conceived and organized the study on the basis of H.K.'s original design. F.L., F.H.-S. and H.K. wrote the manuscript with input from all authors. F.L. performed all analyses and developed the brain atlas app. F.H.-S. established and optimized the tissue dissociation protocol and performed all scRNA-seq and in situ experiments with support from A.P.O., J. Schmidt and C.S. and guidance from M.S. F.L. and F.H.-S. annotated and interpreted the data. T.B. prepared the bulk libraries with guidance from K.M. M.S. established the smRNA-FISH protocol. F.H.-S., A.P.O., D.J., D.S.-C., G.N.S.-D., M.L.M., J. Stundl and S.A.G. collected the samples. A.B.-I., D.M.M., M.E.B. and M.C.R. provided the samples. J.J.S. provided early access to genome assemblies and annotations. A.P.O., M.S., F.M., D.S.-C., A.B.-I., D.M.M. and D.A. provided useful feedback and discussions. H.K. supervised the study and provided funding.

Data Availability

The raw and processed bulk and scRNA-seq data have been deposited to ArrayExpress with the accession numbers E-MTAB-11085 (bulk) and E-MTAB-11087 (single cell) (https://www.ebi.ac.uk/arrayexpress/). The genome annotation files and in situ images have been deposited to Zenodo110 (https://doi.org/10.5281/zenodo.5903844). Information about gene expression, cell type annotation and gene orthology relationships across species can be visualized using the online atlas (https://lampreybrain.kaessmannlab.org/).

Code Availability

All code underlying the published atlas is available on GitHub (https://github.com/f-lamanna/LampreyBrainAtlas/) and Zenodo111 (https://doi.org/10.5281/zenodo.8113793) together with detailed instructions about its usage.

Conflict of Interest

The authors declare no competing interests.


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Additional details

November 2, 2023
January 9, 2024