Scientists have found a key neurological switch that makes the human brain so big

What separates us from humans and 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 this unparalleled growth.

In new research comparing different types of brain organoids – miniaturized masses of brain tissue derived from stem cells – scientists have found a key developmental difference in neural stem cell development between human brain tissue, gorilla and chimpanzee .

Neural stem cells (also called neuroepithelial cells) are a form of multipotent stem cell, giving 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, new research shows.

As neural stem cells transform into specific brain cell types, they change shape, which in turn affects how quickly they can divide and ultimately form neurons. In mice, it was known that such a change in shape occurs in just a few hours, ultimately limiting the amount of brain cells produced by the animals.

(S. Benito-Kwiecinski / MRC LMB / Unit)

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

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

Human neuroepithelial cells take even longer to pass – even a whole week, which allows neurogenesis processes to last longer, which in turn produces more brain cells, more brain tissue and ultimately produces more brains. big (or, as seen here, bigger organoids sitting in a dish).

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

“It is remarkable that a relatively simple evolutionary change in cell form can have major consequences for the evolution of the brain.

In addition to identifying the transition difference, however, organoid analysis 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 efficiently earlier, which shortens the time they can proliferate before becoming progenitor cells. which eventually turn into neurons. .

(S. Benito-Kwiecinski / MRC LMB / Unit)

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

Not only that, but in experiments in which the dynamics of ZEB2 expression were manipulated, the researchers showed that organoids could also be manipulated – organoids in the human brain becoming smaller when the gene was improved, and an organoid gorilla more closely resembling the volume of the human brain. tissue when ZEB2 has been inhibited.

Researchers point out that organoid tissue is never a perfect representation of actual animal organs, so we cannot conclude that ZEB2 activity and inactivity would work exactly the same in the brains of human primates or not. real humans.

Nonetheless, researchers say this is a huge clue to what likely explains much of the difference in brain size between humans and other great apes – and future studies, including experimentation. with transgenic mice or imaging of monkey embryos, could still shed more light. .

“It gives a first idea of ​​what’s different in the developing human brain that sets us apart from our closest living relatives, the other great apes,” Lancaster says.

“I feel like we’ve really learned something fundamental about the issues that have interested me for as long as I can remember – which makes us humans.”

The results are reported in Cell.