Modern humans generate more brain neurons than Neanderthals

Researchers have long been motivated by the query of what distinguishes contemporary humans from earlier species. The Neanderthals, our nearest living ancestors, offer fascinating insights in this regard. The expansion of the brain and the synthesis of new neurons throughout brain development are thought to be key contributors to the evolution of higher cognitive functions in humans. Although modern humans and Neanderthals both have brains of a similar size, little is known about whether the creation of neurons in modern human and Neanderthal brains throughout development may have varied.

The protein TKTL1, which differs from the Neanderthal variant only by one amino acid, is now known to increase basal radial glia, a type of brain progenitor cell, in the modern human brain, according to research from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden. The bulk of the neurons in the growing neocortex, an area of the brain essential for many cognitive functions, are produced by basal radial glial cells. The researchers come to the conclusion that this single human-specific amino acid substitution in TKTL1 underlies a higher neuron production in the developing frontal lobe of the neocortex in modern humans than Neanderthals because TKTL1 activity is particularly high in the frontal lobe of the fetal human brain.

The amino acid sequences of only a tiny number of proteins change between contemporary humans and our ancient ancestors, the Neanderthals and Denisovans. Amino acids are the building blocks of proteins. It is mainly unknown what these changes mean biologically for the growth of the contemporary human brain. In reality, the brains of modern humans and Neanderthals are similar in size, particularly the neocortex. However, it is unclear if this similarity in neocortex size means a similar number of neurons. This question is specifically addressed in the most recent study conducted by Wieland Huttner's research team at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, which he co-founded with Svante Pääbo, director of the Leipzig-based Max Planck Institute for Evolutionary Anthropology, Pauline Wimberger of the University Hospital Dresden, and their colleagues. The protein transketolase-like 1 is the one that the researchers concentrate on because it differs from Neanderthals by just one amino acid in virtually all modern humans (TKTL1). In particular, modern humans' TKTL1 includes an arginine at the sequence position in question, but lysine, a similar amino acid, was present in Neanderthal TKTL1. Neocortical progenitor cells, which give rise to all cortical neurons in the fetal human neocortex, include the gene TKTL1. Notably, the progenitor cells of the frontal lobe have the highest amount of TKTL1.

Wieland Huttner's research team member and study's primary author, Anneline Pinson, set out to determine the importance of this single amino acid alteration for the formation of the neocortex. The Neanderthal or modern human variation of TKTL1 was inserted by Anneline and her colleagues into the neocortex of mouse embryos. They discovered that the modern human form of TKTL1 expanded basal radial glial cells but not the Neanderthal variant, neocortical progenitors thought to be responsible for a larger brain. As a result, mouse embryos with the modern human TKTL1 had more neurons in their brains.

The researchers next looked at how important these effects were for the growth of the human brain. To achieve this, they used human brain organoids, which are tiny organ-like structures that can be produced from human stem cells in cell culture dishes and mimic aspects of early human brain development. They replaced the arginine in modern human TKTL1 with the lysine characteristic of Neanderthal TKTL1. According to Anneline Pinson, "We found that the Neanderthal-type of amino acid in TKTL1 produced fewer basal radial glial cells than the present human-type and, as a result, also fewer neurons." This demonstrates that, despite the fact that we do not know the exact number of neurons in the Neanderthal brain, we may assume that modern humans have more neurons than Neanderthals did in the frontal lobe of the brain, which is where TKTL1 activity is greatest. Additionally, it was discovered by the researchers that modern human TKTL1 affects metabolism by stimulating the pentose phosphate pathway and then increasing fatty acid production. In this manner, it is hypothesized that modern human TKTL1 increases the synthesis of specific membrane lipids required to produce the protracted process of basal radial glial cells that drives their proliferation and, thus, increases the creation of neurons.                                                                                                           

According to Wieland Huttner, who oversaw the study, "this study suggests that the synthesis of neurons in the neocortex during fetal development is stronger in modern humans than it was in Neanderthals, in particular in the frontal lobe." It is tempting to hypothesize that this enhanced frontal lobe-related cognitive capacities in modern humans.

Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG)