Scientists found a key neurological switch that makes human brains so big

What do humans have that separates us from non-human primates, our closest living relatives? One of the biggest differentiators, scientifically speaking, is the size of our much larger brains, and now, we’ve found a key secret behind that unmatched growth.

In new research comparing different types of brain organoids (miniaturized masses of brain tissue that are grown from stem cells), scientists found a key difference in the development of neural stem cells between the brain tissue of humans, gorillas, and chimpanzees.

Neural stem cells (also called neuroepithelial cells) are a form of multipotent stem cells, which give rise to the neurons and glial cells that make up the central nervous system. But how this transition occurs during early brain development is not the same in all primates, the new research shows.

As neural stem cells move into specific types of brain cells, they change their shape, which in turn affects the rate at which they can divide and eventually form neurons. In mice, this shape change was known to occur in a matter of hours, ultimately limiting the number of brain cells the animals produce.

010 biggest brains 2(S. Benito-Kwiecinski / MRC LMB / Cell)

Above: Neural stem cells at five days, with a different and less altered shape in humans (left) compared to apes (right).

Now scientists at the UK Medical Research Council’s Laboratory for Molecular Biology (LMB) have shown that the process takes much longer in primates – in fact, it takes several days. For gorillas and chimpanzees, the delayed shapeshifting gives them about five days to continue generating new neurons.

Human neuroepithelial cells take even longer to transition, even a full week, allowing neurogenesis processes to run longer, which in turn produces more brain cells, more brain tissue, and ultimately, produces larger brains (or, as seen here, larger sitting organoids). in a dish).

“We have found that a delayed change in the shape of cells in the early brain is enough to change the course of development, helping to determine how many neurons are produced,” explains LMB developmental biologist and principal investigator Madeline Lancaster. .

“It is remarkable that a relatively simple evolutionary change in cell shape can have important consequences for brain evolution.”

However, in addition to identifying the difference in transition, analysis of the organoids has also revealed what makes developmental changes possible.

According to the researchers, a gene called ZEB2 plays a central role in regulating the process, causing neural stem cells to change shape and mature effectively earlier, shortening the amount of time they can proliferate before turning into the progenitor cells that eventually form into neurons. .

010 biggest brains 2(S. Benito-Kwiecinski / MRC LMB / Cell)

Above: human brain organoids at five weeks of age, substantially larger than gorilla and chimpanzee organoids (left to right, respectively).

Not only that, but in experiments manipulating the dynamics of ZEB2 expression, the researchers showed that organoids could also be manipulated, with human brain organoids getting smaller and smaller when the gene was enhanced, and a gorilla organoid. which was more like the volume of the human brain. tissue when ZEB2 was inhibited.

The researchers emphasize that organoid tissue is never a perfect representation of real animal organs, so we cannot conclude that ZEB2 activity and inactivity would function in exactly the same way in real human or non-human primate brains.

Nonetheless, the researchers say this is a big clue to what likely explains much of the difference in brain size between humans and other great apes, and future studies, including experimenting with transgenic mice or obtaining images of ape embryos could shed even more light. .

“This provides some of the first insights into the differences in the developing human brain that differentiate us from our closest living relatives, the other great apes,” says Lancaster.

“I feel like we’ve really learned something fundamental about the questions that have interested me for as long as I can remember: what makes us human.”

Findings are reported in Cell.


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