Mouse brains are tiny and smooth. Ferret brains are larger and convoluted. And ferrets, members of the weasel family, could provide the missing link in understanding how we humans acquired our big brains.

Children with microcephaly, whose brains are abnormally small, have a part in the story too. Microcephaly is notorious for its link to the Zika virus, but it can also be caused by mutations in various genes. Some of these genes have been shown to be essential for growth of the cerebral cortex, the part of our brain that handles higher-order thinking.

Reporting in Nature today, a team led by Christopher A. Walsh, MD, PhD, of Boston Children’s Hospital and Byoung-Il Bae, PhD, at Yale University, inactivated the most common recessive microcephaly gene, ASPM, in ferrets. This replicated microcephaly and allowed the team to study what regulates brain size.

“I’m trained as a neurologist, and study kids with developmental brain diseases,” said Walsh in a press release from the Howard Hughes Medical Institute, which gave him a boost to his usual budget to support this work. “I never thought I’d be peering into the evolutionary history of humankind.”

Brain abnormalities as clues to evolution

This isn’t the first time that Walsh, chief of the Division of Genetics and Genomics at Boston Children’s, has connected brain abnormalities with brain evolution. His lab has studied a brain malformation called polymicrogyria and found a gene involved in brain folding that may have enhanced our language ability. More recently, his lab has explored the link between brain evolution and autism.

Walsh now leads the Allen Discovery Center for Human Brain Evolution at Boston Children’s Hospital and Harvard Medical School. The center was founded last year to catalogue the key genes required for human brain evolution and analyze their roles in human behavior and cognition. Microcephaly genes like ASPM are high on the list.

Microcephaly and brain evolution

Ferrets have an outer brain layer that is large and folded, with diverse types of neural progenitor cells – similar to human brains. The smaller brain on the right has had ASPM inactivated, similar to children with microcephaly. (Xenophon Papademetris/Yale University)

In humans, mutations in ASPM shrink the brain by up to half. But in seeking to understand ASPM’s role, mouse models don’t shed much light. A mouse brain is 1,000 times smaller than a human brain, and inactivating ASPM shrinks mouse brains by only about 10 percent. Mice also lack the diverse neural progenitor cell types seen in in the human brain.

So the team turned to ferrets. Ferrets have been used to model brain development for some 30 years, thanks to their larger, more convoluted cortex and ease of breeding. When Walsh, Bae and colleagues inactivated ASPM, the animals’ brains shrunk by up to 40 percent in weight, similar to human microcephaly.

How to grow a brain

Human brain size has tripled over the last seven million years. Most of this growth has occurred in the cerebral cortex. Walsh, Bae and colleagues think the ASPM gene and the ASPM protein it encodes had a hand in this growth.

In the mutant ferrets, they found that ASPM inactivation throws off the timing of neural cell development. Normally, the ASPM protein helps keep neural progenitor cells known as ventricular radial glial cells (VRGs) in the primary germinal zone deep in the brain, where they replicate themselves and churn out more neurons and supporting glial cells.

“ASPM seems to make neural progenitor cells linger in the germinal zone, allowing them to divide more in place,” said Bae, formerly in Walsh’s lab, in a Yale press release.

But in ferrets lacking ASPM, the VRGs start migrating outward from the center of the brain too soon, causing more differentiated progenitors called outer radial glial cells (ORGs) to appear prematurely. The end result is fewer neurons and glial cells and reduced brain volume.

“ASPM controls brain size by acting as a switch to control the number of stem cells in the brain, and this provides for the first time a way to envision how evolution can regulate brain size, through subtle changes in ASPM,” says Walsh.

More to explore

The ASPM protein is part of a cellular structure called the centriole, a complex containing many proteins that is involved in cell division and early embryonic development.

“Many different proteins in this complex show evidence of evolutionary change between humans and other apes, and even some of the show changes between human and Neanderthals,” says Walsh. “This suggests that changes in this complex might be very important.”

More research from the Walsh Lab