Science The point of divergence between modern humans and ancient human nerves: TKTL1

The evolutionary expansion of the cerebral cortex in November
and the consequent increase in the number of neurons are the basis for cognitive enhancement in the process of human evolution[1
].
Endoscopic analysis showed that modern humans had similar brain sizes to Neanderthals, suggesting that their brain volumes were similar
in size to the size of the cerebral cortex.
But whether similarities in the cerebral cortex mean that cortical neurons produce similarities is unknown
.
To uncover the answer to this question, the Wieland B.
Huttner research group at the Max Planck Institute for Molecular Cell Biology and Genetics in Germany published an article in Science titled Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals, Important different effects
of TKTL1 single amino acid on activity in the transketosolase family were found on large-scale neurogenesis in modern humans and ancient humans.


To solve this problem, the authors believe that appropriate models can be used to systematically compare the key developmental features of the cerebral cortex in modern humans and Neanderthals and the different effects
of the key gene variants that control the development of the cerebral cortex.
There are two main types of neural progenitor cells in the developing cerebral cortex, called apical progenitors (APs) and basal progenitors (BPs
).
The authors are interested in genes that influence the behavior of cortical neural progenitor cells, as the abundance of neural progenitor cells and their ability to proliferate determine the number of
cortical neurons produced during development.

With regard to target genes, the authors focus on transketosolase TKTL1[2]
that may affect the behavior of neural progenitor cells in the human fetal cortex.
The reason the authors are concerned about TKTL1 is that one of its TKTL1 precedence is expressed in neural progenitor cells in the cerebral cortex; Secondly, TKTL1 is associated with human tumors and tumor cell proliferation, which may increase the number of neural progenitor cells; Finally, TKTL1 is one
of the few proteins with amino acid substitution.
The 317th of the long subtype TKTL1 is the lysine of amino acid residues in apes and ancient humans, and arginine in modern humans [3].

Therefore, the authors wanted to know whether TKTL1 played a role in the cerebral cortex and affected the behavior of neural progenitor cells, and whether the difference in single amino acids in modern humans and ancient humans had different effects on
the behavior of neural progenitor cells.

Through analysis of published transcriptome databases, the authors found that TKTL1 is expressed in the fetal cerebral cortex and is highly expressed in the frontal lobe
of the brain.
By electro-translating embryos into modern human hTKTL1 and ancient human aTKTL1, respectively, the authors found that overexpressing hTKTL1 instead of aTKTL1 increased the number of
basal radial glia (bRG).
Both bRG and basal intermediate progenitors (bIPs) belong to basal progenitor cells
.
An increase in the number of bRGs promotes an increase
in the number of neurons.
On the other hand, the authors' knockout of hTKTL1 resulted in a decrease
in bRG cell abundance.
Through experiments with brain organoids, the authors found that organoids expressing aTKTL1 have fewer bRG cells as well as neurons
.

So, what is the specific mechanism by which TKTL1 functions? The authors found that hTKTL1 can increase bRG abundance through two metabolic pathways, the pentyl phosphate pathway and fatty acid synthesis
.
Inhibition of the pentyl phosphate pathway and fatty acid synthesis signaling pathway by multiple specific inhibitors completely inhibits the increase in bRG abundance induced by hTKTL1
.
In addition, the authors found that hTKTL1 instead of aTKTL1 promotes the synthesis of fatty acids, which are necessary for the bRG growth process
.

Figure 1 Changes in TKTL1 single-amino acid activity promote the divergence of Neanderthals and modern human neurogenesis processes In general, the authors' work found that the expression of TKTL1 in the human cerebral cortex is particularly high in the frontal lobe of the brain during development, and the single-amino acid activity of hTKTL1 promotes the abundance of basal neural progenitor cells in the frontal lobe of the brain, and promotes the
production of more neurons
in the modern human cerebral cortex 。 The function of hTKTL1 depends on the pentose phosphate pathway and fatty acid synthesis, and inhibition of these metabolic pathways reduces the abundance
of bRG in the neocortical tissue of the fetus.
The work unveiled the key divergent genes and amino acid sites
of neurogenesis between ancient and modern humans.

Original link:

https://doi.
org/10.
1126/science.
abl6422

Plate Maker: Eleven

References

1.
P.
Rakic, Evolution of the neocortex: A perspective from developmental biology.
Nat.
Rev.
Neurosci.
10, 724–735 (2009).
doi: 10.
1038/nrn2719; pmid: 19763105

2.
J.
F.
Coy et al.
, Molecular cloning of tissue-specific transcripts of a transketolase-related gene: Implications for the evolution of new vertebrate genes.
Genomics 32, 309–316 (1996).
doi: 10.
1006/geno.
1996.
0124; pmid: 8838793

3.
K.
Prüfer et al.
, The complete genome sequence of a Neanderthal from the Altai Mountains.
Nature 505, 43–49 (2014).
doi: 10.
1038/nature12886; pmid: 24352235

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