What’s behind humans’ big brains?

One of our species’ defining characteristics is its outsized brain. That heft comes from a bumper crop of neurons born early in development: human brains have three times as many neurons as chimpanzees and gorillas do. Now, researchers are a step closer to understanding this difference. Human brains let their stem cells divide for substantially longer than those of chimps and gorillas before turning on a switch that causes these cells to mature and stop dividing, the study finds. The team also pinpoints a gene called ZEB2 that regulates this timing. When ZEB2, switches on, neural stem cells start elongating their cylindrical shape into more of a cone and winding down neuron production, which sets the final brain size (Cell, 2020, DOI: 10.1016/j.cell.2021.02.050).

“We have identified a difference in the speed of maturation of stem cells in the early human brain compared with chimpanzees and gorillas,” says Madeline A. Lancaster, a developmental biologist at the MRC Laboratory of Molecular Biology.

Lancaster and her colleagues grew 3D clusters of neural stem cells called brain organoids for each of the three species. They found that the cells divide for about 5 days in gorilla and chimpanzee brain organoids, and for about 7 days in human brain organoids, before stopping division and starting maturation. The team’s mathematical modeling shows that this extended cell division accounts for a 1.9-fold larger number of neurons in humans compared to chimps and gorillas–explaining much of the brain size difference between the species.

The researchers then looked for corresponding differences in gene expression and found that ZEB2 begins to be expressed at about the time when the neural stem cells mature in both human and gorilla organoids. When the researchers delayed ZEB2’s expression in the gorilla brain organoids, the organoids grew bigger and looked more like human brain organoids. Conversely, when they triggered the gene to switch on earlier than usual in the human brain organoids, the organoids ended up smaller. Extending that period of neural stem cell division may be a simple mechanism by which humans evolved to have larger brains, the researchers write.

“There are now several papers showing how genes have evolved to increase brain size,” says Alysson Muotri, a stem cell scientist studying brain development at the University of California San Diego. “I think this work adds to that knowledge.”

The researchers next plan to study ZEB2 more closely in order to identify molecular cues that tell the gene when to switch on, Lancaster says.