Mutant Ferrets With 'Severely Shrunken' Brains Reveal Why Ours Are So Big

Genetic engineering shrunk their brains by up to 40 percent.

Cute ferret

Humans have really big brains compared to a lot of animals. It’s sort of our thing. Scientists have presented various hypotheses about how humans developed these big brains — including one about our ancient ancestors eating psychedelic mushrooms — but there’s no scientific consensus on the process that led to human brains doubling in size over 3 million years. A new Nature study of mutant ferrets made to have extra tiny brains, however, just pointed to a genetic quirk in our evolution.

In a paper published Wednesday, researchers report that they’ve found a gene that controls the brain size in ferrets, which they used to genetically engineer animals with 40% smaller brains by weight. This recessive gene, called ASPM (abnormal spindle-like microcephaly-associated), can cause microcephaly in humans, a birth defect characterized by a small head and underdeveloped cerebral cortex.

“Mutations in ASPM are the the most common cause of genetic microcephaly,” Byoung-Il Bae, Ph.D., a neuroscientist at Yale School of Medicine and one of the corresponding authors on the paper, tells Inverse. “ASPM itself has undergone recent evolutionary changes that parallel cortical size. Thus, the role of ASPM is implicated in cortical development and evolution alike.”

ferret brain
Stem cells, shown in green, help neurons find their proper place in the developing brain, forming the cortical structure.

The way that these so-called “ASPM knockout” ferrets’ brains closely resemble microcephalic human brains showed researchers how changes in this gene could have affected human brain size over evolutionary history. This study also showed that ferrets could be a much better model for microcephaly than other animals like mice, which don’t express the condition profoundly enough to give scientists a decent understanding of human brains.

What the study’s authors found was that knocking out ASPM had a significant effect on the ferrets’ brains, resulting in 25 to 40 percent decreases in brain weight — pretty similar to the 50 percent brain weight reduction observed in microcephalic humans. The change in brain size was dependent on the way that ventricular radial glial (VRG) cells in the growing brain developed into outer radial glial (ORG) cells. Knocking out ASPM ramped up the proportion of ORG to VRG cells, which resulted in a smaller cerebral cortex. Notably, the researchers found that while cortical surface area decreased, the thickness remained nearly the same, much like what scientists have observed in humans with microcephaly.

Clumps of neural progenitor cells (in box) differentiate earlier in the ASPM knockout ferret, leading to a smaller cerebral cortex.
Clumps of neural progenitor cells (in box) differentiate earlier in the ASPM knockout ferret, leading to a smaller cerebral cortex.

The important takeaway from this research is that it seems that the longer VRG cells have to organize before converting to ORG cells, the larger the cerebral cortex ends up being.

“Our results support the idea that expansion of cortical surface area during human evolution may have arisen in part from changes to the proliferative time window of VRGs,” write the study’s authors. This means that changes to ASPM over time could have had huge effects for the entire brain, despite ASPM being just one gene.

The researchers say that as ASPM evolved it led to the slower differentiation of VRG and ORG cells, leading to a larger cerebral cortex. This hypothesis for a mechanism of brain evolution is in its early stages, but as more researchers look to the ferret brain as a model for human brain development, scientists will gain more clarity.

Abstract: The human cerebral cortex is distinguished by its large size and abundant gyrification, or folding. However, the evolutionary mechanisms that drive cortical size and structure are unknown. Although genes that are essential for cortical developmental expansion have been identified from the genetics of human primary microcephaly (a disorder associated with reduced brain size and intellectual disability), studies of these genes in mice, which have a smooth cortex that is one thousand times smaller than the cortex of humans, have provided limited insight. Mutations in abnormal spindle-like microcephaly-associated (ASPM), the most common recessive microcephaly gene, reduce cortical volume by at least 50% in humans, but have little effect on the brains of mice; this probably reflects evolutionarily divergent functions of ASPM. Here we used genome editing to create a germline knockout of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell diversity than mice, and closer protein sequence homology to the human ASPM protein. Aspm knockout ferrets exhibit severe microcephaly (25–40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as has been found in human patients3,4, suggesting that loss of ‘cortical units’ has occurred. The cortex of fetal Aspm knockout ferrets displays a very large premature displacement of ventricular radial glial cells to the outer subventricular zone, where many resemble outer radial glia, a subtype of neural progenitor cells that are essentially absent in mice and have been implicated in cerebral cortical expansion in primates. These data suggest an evolutionary mechanism by which ASPM regulates cortical expansion by controlling the affinity of ventricular radial glial cells for the ventricular surface, thus modulating the ratio of ventricular radial glial cells, the most undifferentiated cell type, to outer radial glia, a more differentiated progenitor.