HSINCHU, Taiwan – What makes the human brain so much larger and more complex than the brains of many other mammals?
Scientists have long sought clues in our DNA. Some discoveries show how genetic changes enable the developing brain to produce more cells. Others help explain how long those cells can continue to multiply.
Now, researchers in Taiwan and Japan have uncovered another piece of the evolutionary puzzle: evolution may also have altered the instructions that determine which types of brain-building cells are produced.
Led by researchers at National Yang Ming Chiao Tung University (NYCU) and Academia Sinica, alongside collaborators at Kyoto University, the study identifies a small region of DNA that helps control the production of specialized neural stem cells. The findings suggest that evolution can open up new developmental possibilities without necessarily creating entirely new genes.
A factory with changing instructions
Imagine the developing brain as a factory. Its workers are neural stem cells, which produce the cells that will eventually make up the brain. Evolution can alter this factory in several ways: it can expand the workforce, extend production hours, or change the operating instructions to produce a different mix of workers.
The new research offers evidence for this third possibility.
The team focused on a specialized type of neural stem cell called basal radial glia, or bRG. These cells are especially abundant in developing primate brains but relatively rare in mice. bRGs can divide repeatedly, expanding the population of cells that produce the brain's cerebral cortex - its outer layer, involved in perception, language, memory, and other complex functions. They also contribute to producing nerve cells that communicate across different parts of the cortex.
"What interested us was that the gene already exists in both humans and mice. The important difference may not be the gene itself, but the instructions controlling how it is used during brain development. That gives us another way to understand how evolution could produce different kinds of brains," explained Professor Pei-Shan Hou at the Institute of Anatomy and Cell Biology, NYCU, Taiwan.
Same gene, different instructions
The researchers studied DACH1, a gene shared by humans, monkeys, and mice. They discovered that a small DNA regulatory region acts like a genetic switch, helping control DACH1 activity. One feature of this region is shared among the primates but differs in non-primate vertebrates.
Returning to the factory analogy, the machinery was already in place. Evolution appears to have modified part of its operating manual.
To test the importance of this change, the team used stem cells to grow tiny, three-dimensional models of the developing cerebral cortex of humans and rhesus monkeys in the laboratory. Known as cortical organoids, these brain-like structures reproduce some features of early brain development, allowing scientists to study early developmental processes that are difficult to investigate directly in humans, and to explore how these processes may have changed during evolution.
When researchers removed the regulatory DNA region, the organoids produced fewer cells with a key bRG marker, while other important neural progenitor populations remained largely unchanged. The team then introduced the human regulatory DNA element into developing mouse brains, increasing the number of cells with characteristics associated with bRGs. Together, the experiments suggest that changes in genetic instructions can influence which types of neural progenitors develop in the brain.
Watching brain-building cells change
The team also investigated what happened when DACH1 itself became more active. Using live imaging of developing mouse brain tissue, researchers tracked individual neural stem cells as they divided and produced daughter cells. Experimentally increasing DACH1 activity raised the proportion of daughter cells that developed into bRG-like cells from approximately 4% to nearly 15%.
The researchers also observed shifts in the balance of developing nerve-cell types, including cells associated with connections between the brain's two hemispheres. Further experiments helped explain how DACH1 works: it suppresses another molecular signal involved in the development of neural stem cells. These findings link an evolutionary difference in DNA regulation to changes in the behavior of developing brain cells.
While the findings do not directly explain the evolution of intelligence, they reveal another way evolution may have shaped the primate brain. Brain complexity depends not only on the number of cells produced, but also on the types of cells formed and how they connect.
The next frontier of brain evolution
The discovery points to a broader scientific question: If evolution can change the instructions that control an existing gene, how many other genes have taken on new regulatory roles? And how do these different instructions work together as the brain develops?
Understanding this coordination could help scientists explain how changes in cell production, developmental timing, and cellular identity shaped the evolution of primate brain architecture. It may also improve laboratory models for studying normal and disrupted brain development, though medical applications remain a possibility for the future.
The study offers one new piece of a much larger puzzle. Evolution may have shaped the human brain not only by changing how many cells it produces, but also by changing the instructions that determine what kinds of cells are made.
