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The folding on the right side of this mouse embryo’s cortex reflects the increased growth stimulated by the insertion of a duplicated human gene into that side of the brain.

The folding on the right side of this mouse embryo’s cortex reflects the increased growth stimulated by the insertion of a duplicated human gene into that side of the brain.

Marta Florio and Wieland B. Huttner/Max Planck Institute of Molecular Cell Biology and Genetics

Xeroxed gene may have paved the way for large human brain

Last week, researchers expanded the size of the mouse brain by giving rodents a piece of human DNA. Now another team has topped that feat, pinpointing a human gene that not only grows the mouse brain but also gives it the distinctive folds found in primate brains. The work suggests that scientists are finally beginning to unravel some of the evolutionary steps that boosted the cognitive powers of our species.

 “This study represents a major milestone in our understanding of the developmental emergence of human uniqueness,” says Victor Borrell Franco, a neurobiologist at the Institute of Neurosciences in Alicante, Spain, who was not involved with the work.

The new study began when Wieland Huttner, a developmental neurobiologist at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, and his colleagues started closely examining aborted human fetal tissue and embryonic mice. “We specifically wanted to figure out which genes are active during the development of the cortex, the part of the brain that is greatly expanded in humans and other primates compared to rodents,” says Marta Florio, the Huttner graduate student who carried out the main part of the work.

That was harder than it sounded. Building a cortex requires several kinds of starting cells, or stem cells. The stem cells divide and sometimes specialize into other types of “intermediate” stem cells that in turn divide and form the neurons that make up brain tissue. To learn what genes are active in the two species, the team first had to develop a way to separate out the various types of cortical stem cells.

After months of work, the researchers finally hit upon a solution. They added distinctive fluorescent tags to stem cells so they could isolate each type of cortical cell. Then they surveyed the active genes in each variety of stem cell. The human tissue had 56 genes that their mouse counterparts lacked, the team found. The one that was the most active in dividing human fetal stem cells was ARHGAP11B, a gene already under suspicion for aiding human evolution.

Several years ago, another group had discovered that this gene had arisen after an ancestral gene made an incomplete copy of itself. Because humans had the additional version whereas chimps did not, they concluded that the duplication occurred after the human and chimp lineages split off. Neither mice nor chimps have ARHGAP11B, but modern humans and their ancient relatives, the Denisovans and Neandertals, do. “That it was a human-specific gene duplication made it very exciting,” Huttner says.

After their genetic comparison of human and mice highlighted the same gene, he and his colleagues decided to put ARHGAP11B into developing mice. The number of cortex stem cells nearly doubled in the animals, and their brains sometimes developed folds, the researchers report online today in Science. The folds are not seen in mice but are found in primates. The researchers further discovered that the inserted gene causes some of the mouse’s early brain stem cells to make more intermediate stem cells than the animals usually have. In addition, those intermediates divided more frequently than normal before beginning to convert into neurons. These various effects ultimately increased the size of the mouse brain.

The result “emphasizes the likelihood that this gene was indeed important during mammalian evolution for the design of a new brain, bigger and more complex,” Borrell Franco says. Most likely, he adds there are more genes that are also involved in this design waiting to be discovered.