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Cellular development and evolution of the mammalian cerebellum

Abstract

The expansion of the neocortex, a hallmark of mammalian evolution1,2, was accompanied by an increase in cerebellar neuron numbers3. However, little is known about the evolution of the cellular programs underlying cerebellum development in mammals. In this study, we generated single-nucleus RNA-sequencing data for ~400,000 cells to trace cerebellum development from early neurogenesis to adulthood in human, mouse, and the marsupial opossum. We established a consensus classification of the cellular diversity in the developing mammalian cerebellum and validated it by spatial mapping in the fetal human cerebellum. Our cross-species analyses revealed a largely conserved developmental dynamics of cell type generation, except for Purkinje cells, where we observed an expansion of early-born subtypes in the human lineage. Global transcriptome profiles, conserved cell state markers, and gene expression trajectories across neuronal differentiation show that cerebellar cell type-defining programs have been overall preserved for at least ~160 million years. However, we also identified many orthologous genes that gained or lost expression in cerebellar neural cell types in one of the species, or evolved new expression trajectories during neuronal differentiation, indicating widespread gene repurposing at the cell type level. Altogether, our study unveils shared and lineage-specific gene expression programs governing the development of cerebellar cells, and expands our understanding of mammalian brain evolution.

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Author notes

  1. Ioannis Sarropoulos

    Present address: Wellcome Sanger Institute, Cambridge, UK

  2. These authors contributed equally: Mari Sepp, Kevin Leiss

  3. These authors jointly supervised this work: Ioannis Sarropoulos, Stefan M. Pfister & Henrik Kaessmann

Authors and Affiliations

  1. Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany

    Mari Sepp, Kevin Leiss, Florent Murat, Evgeny Leushkin, Noe Mbengue, Céline Schneider, Julia Schmidt, Nils Trost, Simon Anders, Ioannis Sarropoulos & Henrik Kaessmann

  2. INRAE, LPGP, Rennes, France

    Florent Murat

  3. Hopp-Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Konstantin Okonechnikov, Piyush Joshi, Lisa Spänig, Lena M. Kutscher & Stefan M. Pfister

  4. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

    Konstantin Okonechnikov, Piyush Joshi, Lisa Spänig & Stefan M. Pfister

  5. Developmental Origins of Pediatric Cancer Junior Group, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

    Piyush Joshi, Lisa Spänig & Lena M. Kutscher

  6. Museum für Naturkunde Berlin, Leibniz Institute for Evolution and Biodiversity Science, Berlin, Germany

    Maria Schauer & Peter Giere

  7. NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Philipp Khaitovich

  8. Biosciences Institute, Newcastle University, Newcastle, UK

    Steven Lisgo

  9. Human Brain Tissue Bank, Semmelweis University, Budapest, Hungary

    Miklós Palkovits

  10. BioQuant, Heidelberg University, Heidelberg, Germany

    Simon Anders

  11. Evolutionary Developmental Biology Laboratory, Francis Crick Institute, London, UK

    Margarida Cardoso-Moreira

  12. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

    Stefan M. Pfister

  13. National Center for Tumor Diseases (NCT), Heidelberg, Germany

    Stefan M. Pfister

Authors

  1. Mari Sepp
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Corresponding authors

Correspondence to
Mari Sepp, Kevin Leiss, Ioannis Sarropoulos, Stefan M. Pfister or Henrik Kaessmann.

Supplementary information

Supplementary Information

This file contains Supplementary Methods and additional references.

Reporting Summary

Supplementary Tables

This file contains Supplementary Tables 1-4, 6 and 14. Supplementary Table 1: Samples and libraries. Supplementary Table 2-4: Clustering and annotation of the mouse dataset (2), human dataset (3) and opossum dataset (4). Supplementary Table 6: List of genes analysed by multiplexed single molecule fluorescence in situ hybridisation. Supplementary Table 14. List of genes that gained expression in human astroglia and are enriched in the rhombic lip and posterior ventricular zone progenitors. P-values are from one-sided hypergeometric tests with Benjamini-Hochberg adjustment.

Supplementary Table 5

Cell numbers by sequencing library and annotation categories. Libraries are described as Stage | Tissue ID | batch; and annotations as cell type | state | subtype.

Supplementary Table 7

Gene loadings on principal components 1-15 for the global (PC) and neurons-only (nPC) principal components analyses.

Supplementary Table 8

Conserved cell state marker genes.

Supplementary Table 9

Gene ontology terms associated with the conserved cell state marker genes. P-values are from one-sided hypergeometric tests with Benjamini-Hochberg adjustment for each functional database (source).

Supplementary Table 10

Standardised transcription factor regulon activity scores across cell states in mouse and human.

Supplementary Table 11

Characterization of orthologous genes for expression trajectories during Purkinje and granule cell differentiation.

Supplementary Table 12

Gene ontology terms associated with genes that exhibit trajectory changes or presence/absence (P/A) expression differences. P-values are from one-sided hypergeometric tests with Benjamini-Hochberg adjustment for each functional database (source).

Supplementary Table 13

Presence/absence (P/A) expression differences in cerebellar neural cell types across species.

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Sepp, M., Leiss, K., Murat, F. et al. Cellular development and evolution of the mammalian cerebellum.
Nature (2023). https://doi.org/10.1038/s41586-023-06884-x

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  • Received: 28 November 2021

  • Accepted: 21 November 2023

  • Published: 29 November 2023

  • DOI: https://doi.org/10.1038/s41586-023-06884-x

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