Tracing the Evolution of the “Little Brain”

The evolution of higher cognitive functions in humans was originally linked to the expansion of the neocortex - a brain region responsible for conscious thought, movement and sensory perception, among other things. However, research is increasingly showing that the "small brain" or cerebellum also expanded during evolution and probably contributes to unique human abilities, as Henrik Kaessmann from the Center for Molecular Biology at Heidelberg University (ZMBH) explains.

His research team, together with Stefan Pfister from the Hopp Children's Cancer Center Heidelberg (KiTZ), has now created comprehensive genetic maps of the development of cells in the cerebellum of humans, mice and opossums. 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 in the back of the skull, comprises around 80 percent of all neurons in the entire human brain, it was long regarded as a brain region with a rather simple cellular architecture," explains Henrik Kaessmann. Recently, however, there has been increasing evidence that this structure is highly heterogeneous, according to the molecular biologist. The Heidelberg researchers have now systematically classified all cell types in the developing cerebellum of humans, mice and opossums. To this end, they first collected molecular profiles of almost 400,000 individual cells using single-cell sequencing and applied methods that enable the spatial assignment of cell types.

Based on this data, the scientists found that the proportion of Purkinje cells - large and complex neurons with key functions in the cerebellum - in the human cerebellum at early fetal developmental stages is almost twice as high as in mice and opossums. This increase is mainly due to specific subtypes of Purkinje cells that are the first to emerge during development and that probably communicate with neocortical areas involved in cognitive functions in the mature brain. "One would therefore like to speculate that the expansion of these particular Purkinje cell types in the course of human evolution supports higher cognitive functions in humans," explains Mari Sepp, postdoctoral researcher in Kaessmann's research group "Functional Evolution of Mammalian Genomes".

Using bioinformatic approaches, the researchers also compared the gene expression programs in cerebellar cells of humans, mice and opossums. These programs are defined by the finely tuned activities of a large number of genes that determine the types of cells that differentiate during development. The scientists identified genes with cell type-specific activity profiles that have been conserved across species for at least around 160 million years of evolution. According to Henrik Kaessmann, this suggests that they are important for fundamental mechanisms of identity determination of cell types in the mammalian cerebellum. At the same time, the researchers identified more than a thousand genes with activity profiles that differ between humans, mice and opossums. "At the cell type level, it is quite common for genes to acquire new activity profiles. This means that original genes found in all mammals become active in new cell types in the course of evolution, which can potentially also change the properties of these cells," says Kevin Leiss, a doctoral student in Kaessmann's research group at the time of the work.

Among the genes that have different activity profiles in humans than in mice - the most frequently used model organism in biomedical research - several are associated with neurodevelopmental disorders or brain tumors in childhood, as Stefan Pfister explains. The scientist is Director at KiTZ, heads a research department at the German Cancer Research Center (DKFZ) and works as a pediatric oncologist at Heidelberg University Hospital (UKHD). According to Pfister, the results of the investigations could provide valuable guidance in the search for suitable model systems for further research into such diseases beyond the mouse model.

The research results were published in the scientific journal Nature. In addition to the Heidelberg scientists from the ZMBH and KiTZ, researchers from Berlin, China, France, the UK and Hungary were also involved in the work. The European Research Council funded the work. The research data is available in a public database.

 

Original publication:
M. Sepp, K. Leiss, F. Murat, K. Okonechnikov, P. Joshi, E. Leushkin, L. Spänig, N. Mbengue, C. Schneider, J. Schmidt, N. Trost, M. Schauer, P. Khaitovich, S. Lisgo, M. Palkovits, P. Giere, L. M. Kutscher, S. Anders, M. Cardoso-Moreira, I. Sarropoulos, S. M. Pfister, and H. Kaessmann: Cellular development and evolution of the mammalian cerebellum. Nature (published online 29 November 2023), https://doi.org/10.1038/s41586-023-06884-x

 

Weitere Informationen:
Henrik Kaessmann research group
About KiTZ
Data set as interactive web resource