More brain neurons are generated in modern humans as compared with Neandertals, our closest relatives.
The question of what makes modern humans unique has long been a driving force for researchers. Comparisons with our closest relatives, the Neandertals, therefore provide fascinating insights.
The increase in brain size, and in neuron production during brain development, are considered to be major factors for the increased cognitive abilities that occurred during human evolution. However, while both Neandertals and modern humans develop brains of similar size, very little is known about whether modern human and Neandertal brains may have differed in terms of their neuron production during development.
Researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, now show that the modern human variant of the protein TKTL1, which differs by only a single amino acid from the Neandertal variant, increases one type of brain progenitor cells, called basal radial glia, in the modern human brain. Basal radial glial cells generate the majority of the neurons in the developing neocortex, a part of the brain that is crucial for many cognitive abilities. As TKTL1 activity is particularly high in the frontal lobe of the foetal human brain, the researchers concluded that this single human-specific amino acid substitution in TKTL1 underlies a greater neuron production in the developing frontal lobe of the neocortex in modern humans than Neandertals.
Only a small number of proteins have differences in the sequence of their amino acids – the building blocks of proteins – between modern humans and our extinct relatives, the Neandertals and Denisovans. The biological significance of these differences for the development of the modern human brain is largely unknown. In fact both modern humans and Neandertals feature a brain, and notably a neocortex, of similar size, but whether this similar neocortex size implies a similar number of neurons remains unclear.
The research group of Wieland Huttner, one of the founding directors of the MPI-CBG, carried out in collaboration with Svante Pääbo, director at the Max Planck Institute for Evolutionary Anthropology in Leipzig, and Pauline Wimberger of the University Hospital Dresden and their colleagues, focused on one of these proteins that presents a single amino acid change in essentially all modern humans compared to Neandertals, the protein transketolase-like 1 (TKTL1).
Specifically, in modern humans TKTL1 contains an arginine at the sequence position in question, whereas in Neandertal TKTL1 it is the related amino acid lysine. In the foetal human neocortex, TKTL1 is found in neocortical progenitor cells, the cells from which all cortical neurons derive. Notably, the level of TKTL1 is highest in the progenitor cells of the frontal lobe.
Modern human TKTL1 develops more neurons
Anneline Pinson, the lead author of the study and researcher in the group of Wieland Huttner, set out to investigate the significance of this one amino acid change using mouse models. She said: “We found that with the Neandertal-type of amino acid in TKTL1, fewer basal radial glial cells were produced than with the modern human-type and, as a consequence, also fewer neurons,” says Anneline Pinson. “This shows us that even though we do not know how many neurons the Neandertal brain had, we can assume that modern humans have more neurons in the frontal lobe of the brain, where TKTL1 activity is highest, than Neandertals.”
Study supervisor Wieland Huttner added: “This study implies that the production of neurons in the neocortex during foetal development is greater in modern humans than it was in Neandertals, in particular in the frontal lobe. It is tempting to speculate that this promoted modern human cognitive abilities associated with the frontal lobe.”
The study appears in the journal Science.
Image: Microscopy picture of a dividing basal radial glial cell, a progenitor cell type that generates neurons during brain development. Modern human TKTL1, but not Neandertal TKTL1, increases basal radial glia and neuron abundance. Credit: Pinson et al., Science 2022 / MPI-CBG