Dataset Information

Cellular development and evolution of the mammalian cerebellum.

ABSTRACT: The expansion of the neocortex, a hallmark of mammalian evolution^1,2, was accompanied by an increase in cerebellar neuron numbers³. However, little is known about the evolution of the cellular programmes underlying the development of the cerebellum in mammals. In this study we generated single-nucleus RNA-sequencing data for around 400,000 cells to trace the development of the cerebellum 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 largely conserved developmental dynamics of cell-type generation, except for Purkinje cells, for which 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 programmes 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. In sum, our study unveils shared and lineage-specific gene-expression programmes governing the development of cerebellar cells and expands our understanding of mammalian brain evolution.

SUBMITTER: Sepp M

PROVIDER: S-EPMC10808058 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Cellular development and evolution of the mammalian cerebellum.

Sepp Mari M Leiss Kevin K Murat Florent F Okonechnikov Konstantin K Joshi Piyush P Leushkin Evgeny E Spänig Lisa L Mbengue Noe N Schneider Céline C Schmidt Julia J Trost Nils N Schauer Maria M Khaitovich Philipp P Lisgo Steven S Palkovits Miklós M Giere Peter P Kutscher Lena M LM Anders Simon S Cardoso-Moreira Margarida M Sarropoulos Ioannis I Pfister Stefan M SM Kaessmann Henrik H

Nature 20231129 7996

The expansion of the neocortex, a hallmark of mammalian evolution<sup>1,2</sup>, was accompanied by an increase in cerebellar neuron numbers<sup>3</sup>. However, little is known about the evolution of the cellular programmes underlying the development of the cerebellum in mammals. In this study we generated single-nucleus RNA-sequencing data for around 400,000 cells to trace the development of the cerebellum from early neurogenesis to adulthood in human, mouse and the marsupial opossum. We esta ...[more]

PMID: 38029793

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Project description:In mammals, imprinted gene expression results from the sex-specific methylation of imprinted control regions (ICRs) in the parental germlines. Imprinting is linked to therian reproduction, that is, the placenta and imprinting emerged at roughly the same time and potentially co-evolved. We assessed the transcriptome-wide and ontology effect of maternally versus paternally methylated ICRs at the developmental stage of setting of the chorioallantoic placenta in the mouse (8.5dpc), using two models of imprinting deficiency including completely imprint-free embryos. Paternal and maternal imprints have a similar quantitative impact on the embryonic transcriptome. However, transcriptional effects of maternal ICRs are qualitatively focused on the fetal-maternal interface, while paternal ICRs weakly affect non-convergent biological processes, with little consequence for viability at 8.5dpc. Moreover, genes regulated by maternal ICRs indirectly influence genes regulated by paternal ICRs, while the reverse is not observed. The functional dominance of maternal imprints over early embryonic development is potentially linked to selection pressures favoring methylation-dependent control of maternal over paternal ICRs. We previously hypothesized that the different methylation histories of ICRs in the maternal versus the paternal germlines may have put paternal ICRs under higher mutational pressure to lose CpGs by deamination. Using comparative genomics of 17 extant mammalian species, we show here that, while ICRs in general have been constrained to maintain more CpGs than non-imprinted sequences, the rate of CpG loss at paternal ICRs has indeed been higher than at maternal ICRs during evolution. In fact, maternal ICRs, which have the characteristics of CpG-rich promoters, have gained CpGs compared to non-imprinted CpG-rich promoters. Thus, the numerical and, during early embryonic development, functional dominance of maternal ICRs can be explained as the consequence of two orthogonal evolutionary forces: pressure to tightly regulate genes affecting the fetal-maternal interface and pressure to avoid the mutagenic environment of the paternal germline.

Dataset Information

Cellular development and evolution of the mammalian cerebellum.

Publications

Cellular development and evolution of the mammalian cerebellum.

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