Genetically altering ferrets gives new insight into brain development and evolution.
Humans are blessed with relatively large brains. And, during the past 7 million years — a short time span in evolutionary terms — the size of our brains has tripled.
The cerebral cortex, the convoluted and folded outer layer, is particularly so in humans. Exactly why and how our brains became so darned fancy is a point of much debate and the evidence is currently scant.
Finding clues as to genetic and biological shifts that occurred millions of years ago is similar to looking for a needle in a haystack on the other side of the universe. Every so often, however, Lady Serendipity smiles on scientists.
Recently, researchers from a number of institutions, including the Howard Hughes Medical Institute in Chevy Chase, MD, Yale University in New Haven, CT, and Boston Children's Hospital in Massachusetts, conducted a series of studies looking at microcephaly.
Their studies were fruitful and further our understanding of microcephaly, but they also inched us closer to that needle in the distant haystack. Their findings were recently published in the journal Nature.
"I'm trained as a neurologist and study kids with developmental brain diseases," explains Dr. Christopher Walsh, from Boston Children's Hospital. "I never thought I'd be peering into the evolutionary history of humankind."
How to research microcephaly
Babies with microcephaly have a much smaller head than normal, and their cerebral cortex is not formed correctly. This condition is often genetic, although recently, it has also been linked to the Zika virus.
How and why the cortex does not form properly is not fully understood. One reason why exploring this topic is so tricky is the lack of a good model; a mouse model is most often used, but it is not fit for purpose.
Mouse brains are, as you might expect, tiny. Also, mice do not enjoy the same diverse selection of brain cells as humans, and their cortex is much smoother.
The gene most commonly involved in microcephaly is one that codes for a protein known as Aspm. When this gene is mutated, a human's brain will be around half the normal size.
However, in mice without the gene — called Aspm knockout mice — their brains shrink by just one tenth. This barely detectable change is of little use to scientists.
On the hunt for a better model of microcephaly, the researchers — who were led by Dr. Walsh and Byoung-Il Bae, from Yale University — turned to ferrets.
This might, at first, seem to be an odd choice of animal, but it makes good sense; ferrets are larger and have a complex cortex with the same range of cell types as humans. Also, like mice, they breed quickly and freely.
As Dr. Walsh explains, "On the face of it, ferrets may seem a funny choice, but they have been an important model for brain development for 30 years."
Although ferrets have proven useful previously, little is known about ferret genetics, so creating an Aspm knockout version of the animal would be challenging. Dr. Walsh, however, was undeterred; he secured funding and got to work.
The Aspm knockout ferret is only the second knockout ferret that humanity has ever created.
As expected, Aspm knockout ferrets' brains were up to 40 percent smaller than normal, bringing it much closer in line with the human version of microcephaly. And, as with human microcephaly, the cortical thickness was unchanged.
A clue to brain evolution
Aside from designing a new and useful model for human microcephaly, the scientists also dipped their toes into a much more intractable problem: how did we evolve such big brains?
They investigated how the loss of Apsm impacted the ferrets' brains in the way that it did. The defects were traced back to changes in the way that radial glial cells behaved.
Radial glial cells develop from neuroepithelial cells, which are the stem cells of the nervous system. These are capable of developing into a number of different cell types in the cortex.
Starting near the developing brain ventricles, radial glial cells move toward the forming cortex. As these cells move farther away from their start point, they slowly lose their ability to develop into different types of brain cells.
The team found that a lack of Apsm caused radial glial cells to detach from the ventricles more readily and began their migration early.
Once the timing was off, the ratio of radial glial cells to other cell types went skew-whiff, resulting in fewer nerve cells in the cortex. Apsm acts as a regulator, dialing up or down the overall number of cortical neurons. And, herein lies the clue to human brain evolution.
"Nature had to solve the problem of changing the size of the human brain without having to re-engineer the whole thing."
Apsm alters brain development in this way by influencing the function of centrioles, or cellular structures involved in cell division. Without Apsm, the centrioles don't do their job properly.
Recently, a few genes involved in regulating centriole proteins, including Apsm, have undergone evolutionary changes. Dr. Walsh believes that it may be these genes that distinguish us from chimpanzees, or our distant cousins the Neanderthals.
"It makes sense in retrospect," Dr. Walsh says. "The genes that put our brains together during development must have been the genes that evolution tweaked to make our brains bigger."
By altering this one gene, radial glial cells' migration can be altered and the cortex can grow larger. These studies provide a new model for microcephaly and a new insight into the origin of our bulging brain.