Do all animals have brains 1

A gene for a more brain

Research Report 2015 - Max Planck Institute for Molecular Cell Biology and Genetics

Neural stem and progenitor cells and neocortex expansion in development and evolution (Huttner Lab)
The gene ARHGAP11B only occurs in humans, causes the reproduction of basal brain stem cells and can trigger a cerebral cortex fold. This causes the cerebrum, which is responsible for higher cognitive performance, to expand. The expression of the transcription factor Pax6 also plays an important role: it is also through this that the stem cells for the nerve cells of the cerebral cortex multiply - a prerequisite for a larger brain. This process can even be simulated in mice: the mouse stem cells then behave in a similar way to the stem cells in the primate and human brain.

If you compare the human brain with that of a mouse, one difference immediately catches the eye: the human brain is folded, whereas the brain of a mouse is smooth. In addition, the human brain is much larger in relation to the body than that of the mouse. The neocortex in particular is much more pronounced in humans - this area of ​​the cerebrum is responsible, among other things, for the fact that we can dream, speak or think complexly. A comparison with our close relatives is even more interesting. We humans have around 99 percent of the genes in common with the chimpanzee, for example. Despite these great similarities, an important difference is again at the brain level: that of humans is three times as large as that of chimpanzees. In the course of evolution, changes must have taken place in the human genome and thus in the cell biological and genetic factors of the development of the central nervous system, which in turn have led to pronounced brain growth and the expansion of the neocortex. This small difference is crucial, because ultimately the size of the human brain and its pronounced cerebral cortex make a decisive contribution to what makes us human.

In order to search for the factors that trigger and control these differences between the human brain and that of other living beings, researchers led by Wieland Huttner, Director and Research Group Leader at the MPI for Molecular Cell Biology and Genetics, managed to do something that no one had previously achieved: with which special subpopulations of brain stem cells can be obtained from the developing cerebrum [1]. The scientists first isolated various stem and progenitor cell types from fetal cerebral tissue from humans and mice. Then the researchers compared the genes that are active in these diverse cell types. They were able to identify 56 genes that occur in humans but not in mice and that could play a role in brain development.

It was noticed that the gene ARHGAP11B, which was not found in any primate other than humans, is particularly active in the so-called basal brain stem cells. These cells have been particularly important for the expansion of the cerebral cortex in the course of evolution. Huttner's group has long been interested in the secrets of human brain evolution. In recent years, researchers have made several discoveries that have helped us understand the evolutionary development of a large brain. In 2010, for example, they identified a new type of stem cell in the outer germinal zone of the brain.

Spectacular discovery: the human-specific gene also works in mice

To test if the gene ARHGAP11B actually ensures that more basal brain stem cells are formed in humans and that the cerebrum grows, the researchers cross-checked and introduced the gene into mouse embryos. The result was spectacular: In fact, the human-specific gene in the smaller mouse brain caused significantly more basal brain stem cells to form and, in half of the cases, even folds of the otherwise smooth cerebral cortex were formed - exactly as they are particularly pronounced in humans (Fig. 1). So comes the gene ARHGAP11B play a key role in the evolutionary expansion of the human cerebral cortex. It is the first human-specific gene that has been shown to make a significant contribution to the multiplication of the important basal brain stem cells and to trigger cerebral cortex folding.

Remarkably, the gene existed ARHGAP11B even in the genome of Neanderthals and Denisovans, as shown by data from researchers involved in the study led by Svante Pääbo from the Max Planck Institute for Evolutionary Anthropology in Leipzig. Neanderthals also had a brain similar to that of humans.

Next in sight: Pax6

The key role of the human-specific gene ARHGAP11B in the evolutionary expansion of the cerebral cortex is a great discovery, but the researchers had other gene candidates whose role in brain development they wanted to investigate more closely. Among other things, she was interested in the specific expression of the transcription factor Pax6: During the development of a human brain, this gene is very active in the basal brain stem cells, but significantly less in mice [2]. This leads to different behavior of these cells in humans and mice: In humans, basal progenitor cells go through several rounds of cell division, whereby the number of nerve cells increases considerably and with it the size of the neocortex. In mice, on the other hand, these precursor cells usually only divide once, which results in a lower number of nerve cells. The idea was to express the transcription factor Pax6 to imitate mouse embryos in the same way as in the developing human brain and see whether the behavior of these mouse cells then resembles that of precursor cells in the developing primate brain. Will more nerve cells arise? Will the cerebral cortex expand in the mouse too?

For this purpose, researchers in Wieland Huttner's group developed a new type of transgenic mouse line. In these mice, the researchers were now able to express Pax6 change in the cortical stem cells in such a way that it is maintained in the basal progenitor cells as in humans. In fact, this manipulation caused the basal precursor cells of the mouse embryos to divide several times - similar to that in primates. The result was not only a larger population of basal progenitor cells; more cortical nerve cells were also produced, particularly for the top layer of the cerebral cortex - another feature of a more sophisticated neocortex (Fig. 2).

The study thus shows that the altered activity of a single key gene can make a big difference in brain development. The genes ARHGAP11B and Pax6 are just pieces of the mosaic in a big puzzle: A future challenge will be to get a comprehensive and holistic view of all the molecular changes that have made the human brain so big.

Bibliography

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Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion
Science 347 (6229), 1465-1470 (2015)
Kuan Wong, F .; Fei, J.-F. ; Mora-Bermúdez, F .; Taverna, E .; Haffner, C .; Fu, J., Anastassiadis, K .; Francis Stewart, A .; Huttner, W.B.
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