Summary: New research reveals the cerebellums significant role in the evolution of human cognitive functions. The study mapped the genetic development of cerebellar cells in humans, mice, and opossums, uncovering both ancestral and unique cellular characteristics.

Key findings include the increased proportion of specific Purkinje cells in humans, potentially linked to higher cognitive functions, and the identification of over 1,000 genes with varying activity profiles across species, some related to neurodevelopmental disorders.

Key Facts:

Source: Heidelberg University

The evolution of higher cognitive functions in human beings has so far mostly been linked to the expansion of the neocortex a region of the brain that is responsible, inter alia, for conscious thought, movement and sensory perception.

Researchers are increasingly realizing, however, that the little brain or cerebellum also expanded during evolution and probably contributes to the capacities unique to humans, explains Prof. Dr Henrik Kaessmann from the Center for Molecular Biology of Heidelberg University.

His research team has together with Prof. Dr Stefan Pfister from the Hopp Childrens Cancer Center Heidelberg generated comprehensive genetic maps of the development of cells in the cerebella of human, mouse and opossum.

Comparisons of these data reveal both ancestral and species-specific cellular and molecular characteristics of cerebellum development spanning over 160 million years of mammalian evolution.

Although the cerebellum, a structure at the back of the skull, contains about 80 percent of all neurons in the whole human brain, this was long considered a brain region with a rather simple cellular architecture, explains Prof. Kaessmann.

In recent times, however, evidence suggesting a pronounced heterogeneity within this structure has been growing, says the molecular biologist.

The Heidelberg researchers have now systematically classified all cell types in the developing cerebellum of human, mouse and opossum. To do so they first collected molecular profiles from almost 400,000 individual cells using single-cell sequencing technologies. They also employed procedures enabling spatial mapping of the cell types.

On the basis of these data the scientists noted that in the human cerebellum, the proportion of Purkinje cells large, complex neurons with key functions in the cerebellum is almost double that of mouse and opossum in the early stages of fetal development.

This increase is primarily driven by specific subtypes of Purkinje cells that are generated first during development and likely communicate with neocortical areas involved in cognitive functions in the mature brain.

It stands to reason that the expansion of these specific types of Purkinje cells during human evolution supports higher cognitive functions in humans, explains Dr Mari Sepp, a postdoctoral researcher in Prof. Kaessmanns research group Functional evolution of mammalian genomes.

Using bioinformatic approaches, the researchers also compared the gene expression programmes in cerebellum cells of human, mouse and opossum. These programmes are defined by the fine-tuned activities of a myriad of genes that determine the types into which cells differentiate in the course of development.

Genes with cell-type-specific activity profiles were identified that have been conserved across species for at least about 160 million years of evolution.

According to Henrik Kaessmann, this suggests that they are important for fundamental mechanisms that determine cell type identities in the mammalian cerebellum. At the same time, the scientists identified over 1,000 genes with activity profiles differing between human, mouse and opossum.

At the level of cell types, it happens fairly frequently that genes obtain new activity profiles. This means that ancestral genes, present in all mammals, become active in new cell types during evolution, potentially changing the properties of these cells, says Dr Kevin Leiss, who at the time of the studies was a doctoral student in Prof. Kaessmanns research group.

Among the genes showing activity profiles that differ between human and mouse the most frequently used model organism in biomedical research several are associated with neurodevelopmental disorders or childhood brain tumours, Prof. Pfister explains. He is a director at the Hopp Childrens Cancer Center Heidelberg, heads a research division at the German Cancer Research Center and is a consultant paediatric oncologist at Heidelberg University Hospital.

The results of the study could, as Prof. Pfister suggests, provide valuable guidance in the search for suitable model systems beyond the mouse model to further explore such diseases.

The research results were published in the journal Nature. Also participating in the studies apart from the Heidelberg scientists were researchers from Berlin as well as China, France, Hungary, and the United Kingdom. The European Research Council financed the research. The data are available in a public database.

Author: Ute Mueller-Detert Source: Heidelberg University Contact: Ute Mueller-Detert Heidelberg University Image: The image is credited to Neuroscience News

Original Research: Closed access. Cellular development and evolution of the mammalian cerebellum by Henrik Kaessmann et al. Nature

Abstract

Cellular development and evolution of the mammalian cerebellum

The expansion of the neocortex, a hallmark of mammalian evolution, was accompanied by an increase in cerebellar neuron numbers. 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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The Cerebellum's Role in Human Cognitive Evolution - Neuroscience News