DACH1 Switch Steers Primate Brain Cell Production

The gene is old. The switch is the new part. Researchers at National Yang Ming Chiao Tung University and Academia Sinica in Taiwan, working with collaborators at Kyoto University in Japan, report in Science Advances that a small region of regulatory DNA controls the gene DACH1 and, through it, the production of basal radial glia. Those stem cells, called bRG, are abundant in developing primate brains and rare in mice, and they divide repeatedly to build the cerebral cortex.

One feature of that regulatory region is shared among primates and differs in non-primate vertebrates. DACH1 itself is not a primate invention. Humans, monkeys and mice all carry it. The difference the team found sits in the instructions that govern when and how strongly the gene is used during brain development, not in the gene's own code.

"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," said Professor Pei-Shan Hou of NYCU's Institute of Anatomy and Cell Biology. "That gives us another way to understand how evolution could produce different kinds of brains."

The tests ran in both directions. The team grew cortical organoids, three-dimensional models of the developing cortex, from human and rhesus monkey stem cells. When the researchers removed the regulatory DNA region, the organoids produced fewer cells carrying a key bRG marker, and other neural progenitor populations stayed largely unchanged. When they put the human regulatory element into developing mouse brains, the number of cells with bRG characteristics rose.

Turning the gene itself up produced the sharpest number in the paper. Using live imaging of developing mouse brain tissue, the team tracked individual stem cells as they divided. Raising DACH1 activity lifted the proportion of daughter cells that became bRG-like cells from approximately 4 percent to nearly 15 percent. The researchers also traced the mechanism one step down: DACH1 works in part by suppressing another molecular signal involved in neural stem cell development.

The paper doesn't claim to explain intelligence, and the authors don't either. What it establishes is a third route for brain evolution, beside making more cells and letting cells divide for longer. Evolution can also change the mix, rewriting which kinds of brain-building cells a developing cortex produces. How many other genes carry primate-specific instruction changes like this one is now an open question with a method attached to it.

The bRG cells matter because of what they build. They don't just add bulk to the cortex. They also produce nerve cells that connect different parts of the cortex to each other, including the connections between the brain's two hemispheres, and the team saw the balance of those nerve-cell types shift when DACH1 activity changed. A switch that changes the cell mix changes the wiring diagram, not only the cell count.

The organoid work is the part other labs can reuse first. A human cortical organoid grown for 76 days, with DACH1-producing cells tagged so they glow green, gives researchers a bench model where a single regulatory change can be added or removed and the consequences counted cell by cell. The authors are careful about the distance to medicine: better models of normal and disrupted brain development are a possibility for the future, not a therapy on a schedule. The finding's immediate value is narrower and stronger. It's a worked example, with numbers, of evolution editing the manual instead of the machine.