Evolution May Have Rewritten Brain-Building Instructions, Not Just Genes, in Primate Cortex Development

In a laboratory dish, researchers grew tiny three-dimensional models of the developing cerebral cortex from stem cells, some human and some from rhesus monkeys. Then they cut out one small stretch of regulatory DNA and counted what changed. The organoids made fewer cells carrying a key marker of basal radial glia, a specialized kind of neural stem cell. Other important progenitor populations stayed largely the same.

That result sits at the center of a study from researchers at National Yang Ming Chiao Tung University (NYCU) and Academia Sinica in Taiwan, working with collaborators at Kyoto University in Japan. It addresses an old question: why is the human brain so much larger and more complex than that of any other mammal? Earlier work in DNA has shown how genetic changes let the developing brain produce more cells, and how long those cells can keep multiplying. This team proposes a third route: evolution may have altered the instructions that determine which types of brain-building cells get made.

The researchers describe the developing brain as a factory whose workers are neural stem cells. Evolution could enlarge the workforce, extend production hours, or rewrite the operating instructions so a different mix of workers emerges. The new work offers evidence for the third option.

The cells in question, basal radial glia or bRG, are abundant in developing primate brains but relatively rare in mice. They divide repeatedly, expanding the pool of cells that build the cerebral cortex, the brain's outer layer, which is involved in perception, language, memory and other complex functions. They also help produce nerve cells that communicate across different regions of the cortex.

The gene the team studied is DACH1, which humans, monkeys and mice all carry. What differs is a small regulatory region of DNA that acts like a switch controlling the gene's activity. One feature of that region is shared among primates but differs in non-primate vertebrates. As Professor Pei-Shan Hou of NYCU's Institute of Anatomy and Cell Biology put it, the important difference may not be the gene itself but the instructions governing how it is used during brain development.

The team also ran the experiment in the other direction. When they introduced the human version of the regulatory element into developing mouse brains, the number of cells with bRG-like characteristics rose. They then tracked individual neural stem cells through live imaging of developing mouse brain tissue, watching them divide and produce daughter cells. Experimentally boosting DACH1 activity raised the share of daughter cells that became bRG-like from roughly 4% to nearly 15%.

The researchers also saw shifts in the balance of developing nerve-cell types, including cells linked to connections between the brain's two hemispheres. Further experiments suggested how DACH1 works: it suppresses another molecular signal involved in neural stem cell development. Together, the findings tie an evolutionary difference in DNA regulation to changes in how developing brain cells behave.

The authors are careful about the limits. The findings do not directly explain the evolution of intelligence. They add another mechanism, since brain complexity depends not only on how many cells are produced but on what types form and how they connect.

The next question is scale: if evolution can change the controls on an existing gene, how many other genes have taken on new regulatory roles, and how do those controls work together as the brain develops? Answering that could clarify how cell production, timing and cell identity shaped primate brain architecture. It may also improve laboratory models of normal and disrupted brain development, though medical applications remain only a future possibility.