Science is another masterpiece! The latest Nobel laureate Pääbo has collaborated to uncover the differences between modern humans and Neanderthals' neocortex of the brain

iNature

Neanderthal brains are similar in size to
those of modern humans.
However, it is unclear
whether similar neocortical sizes mean the production of similar neocortical neurons.

On September 9, 2022, the Max Planck Institute for Molecular Cell Biology and Genetics Wieland B.
Huttner and the Max Planck Institute for Evolutionary Anthropology Svante Pääbo collaborated in Science to publish online "Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than.
" Neanderthals' research paper, which sought to examine potential differences
in neurogenesis during neocortical development.
The difference between modern human TKTL1 (TKTL1) and Neanderthals TKTL1 is the amino acid substitution
of lysine to arginine.

By overexpressing in the neocortex of developing mice and ferrets, knocking out in fetal human neocortex tissue, and genome-edited brain organoids, the study found that the modern human variant, hTKTL1, rather than the Neanderthal variant, increased the richness of basal radial radial glial cells (bRG) but not the richness
of intermediate progenitor cells (bIPs).
bRG produces more neocortical neurons than bIPs
.
The hTKTL1 effect requires the pentose phosphate pathway and fatty acid synthesis
.
Inhibition of these metabolic pathways reduces the abundance of bRG in fetal neocortical tissue.

In summary, the data from the study suggest that neocortical neurogenesis in modern humans differs from Neanderthals
.

Whether and how modern man's cognitive abilities differ from those of extinct hominins (such as Neanderthals) remains a controversial issue
.
The discovery of crafts and art, speculated to have originated in Neanderthals, has intensified the controversy
.
Cognitive abilities are mainly present in the neocortex of the brain, the largest, recently evolved part of the brain and found only in
mammals.
The evolutionary expansion of the neocortex and the consequent increase in the number of neurons produced are considered to be the basis for the
increase in cognitive ability during human evolution.
Analysis of endocasts showed that the intracranial volume was similar in modern humans and Neanderthals, indicating similar sizes to the brain and neocortex
.
However, it is unclear
whether similar neocortical sizes mean the production of similar neocortical neurons.
One way to solve this problem is to compare the key features of neocortical development in modern and Neanderthals, use appropriate model systems, and focus on the behavior
of modern and Neanderthals to control key gene variants of neocortical development.
Of particular interest here are genes that influence the behavior of neural progenitor cells in the neocortex of the fetus, as their abundance and proliferative capacity determine the number of
cortical neurons produced during development.
TKTL1 and Paleoprotein cortical neurogenesis (Figure from Science) There are two main types of neural progenitor cells in the developing neocortex, called apical progenitor cells (APs) and basal progenitor cells (BPs
).
APs are a major category and are located in the ventricular region (VZ
).
After neurogenesis, the main AP type is the apical (or ventricular) radial glial cells (aRG
).
aRG produces mainly BP (the second type of neural progenitor cell), rather than producing neurons
.
Newborn BP migrates to the subventricular region (SVZ), where they produce most cortical neurons
.
There are two types of BP described as basal intermediate progenitor cells (bIPs) and basal (or extra) radial glial cells (bRG
).
In mammals with small and brainless neocortexes, such as mice, about 90% of BP is neurogenic bIPs, which usually divide to produce two neurons at once
.
bRG accounts for only about 10%
of neocortical BPs in embryonic mice.
In contrast, in ferrets and primates such as marmosets, macaques and humans, bRG accounts for about
50% of the BP pool.
The increase in the relative abundance of bRG is thought to drive an increase in cortical neuronal production, a hallmark
of the evolution of the neocortex in humans.
Modern human TKTL1, rather than ancient human TKTL1, increases the richness of mitotic bRG when expressed in the neocortex of embryonic mice (Figure from Science) Compared to bIPs, the neurogenic division of bRG is usually asymmetrical, producing a bRG (self-renewal) and a neuron
.
This pattern of cell division reflects the presence of bRG cell polarity, an obvious foundational process that is lacking in bIPs
.
Over time, bRGs produce more cortical neurons than bIPs
.
One gene that may affect the behavior of human neocortical neural progenitor cells in the fetus is transketolase-like 1 (TKTL1
).
TKTL1 belongs to the enzyme of the transketomase
family.
It acts on the pentose phosphate pathway (PPP), a metabolic pathway
associated with glycolysis.
The researchers focused on TKTL1 because: (i) TKTL1 preferentially expressed in neural progenitor cells of the human neocortex of the fetus, including bRG; (ii) TKTL1 is associated with human tumors and tumor cell proliferation and may also increase the number of neural progenitor cells; (iii) TKTL1 is one of the few proteins with amino acid substitution found in almost all modern humans but not
in extinct hominins, Neanderthals and Denisovans and other primates.
The 317th amino acid residue in the long subtype TKTL1 (corresponding to the 261st amino acid residue in the short subtype) is lysine in apes and hominin humans and arginine
in modern humans.
Thus, the study examined whether (i) TKTL1 plays a role in neocortical development and affects neural progenitor cell behavior, and (ii) whether ancient human TKTL1 (aTKTL1) and modern human TKTL1 (hTKTL1) have a similar effect on
neural progenitor cells during neocortical development.
The study found that hTKTL1 instead of aTKTL1 increased the abundance of bRG during neocortical development, rather than the abundance
of bIPs.
Researchers believe that modern humans produce more
neocortical neurons during neurogenesis than Neanderthals.

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