Genetic Tweak Makes Mouse Brain Cells Behave Like Primates'

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Described as the “substrate of human mental prowess,” the neocortex is the mammalian brain’s latest and greatest addition. The hub of higher mental functions, since its emergence it has undergone expansion in several mammal lineages, but most notably our own. This enlargement, and therefore differences between mammalian species, have been linked to increased abundance and proliferation of so-called progenitor cells that develop into specialized brain cells.

But what’s behind this increased capacity to divide? Certainly not one single thing, research is showing us, but slowly scientists are beginning to piece together this complicated puzzle. Adding to our understanding, a new study has found that prolonging expression of just one gene in a specific set of neural progenitors caused the developing mouse brain to take on a more primate-like appearance.

By mimicking the expression pattern seen in human brain development, the early cells changed their behavior and exhibited increased growth. Although the researchers didn’t specifically measure brain size, enhanced proliferation would be a trait required for brain enlargement.

“The evolutionary expansion of the neocortex is a hallmark of species with higher cognitive functions,” lead researcher Wieland Huttner from the Max Planck Institute of Molecular Cell Biology and Genetics said in a statement. “Our findings contribute to our understanding of the molecular mechanisms underlying this expansion.”

As the mammalian brain develops, so-called neural progenitors divide and ultimately specialize into all of the different cell types of the brain. Although there are numerous progenitors, the researchers of the present study were interested in a type called basal progenitors due to the fact that they exhibit different behaviors between smaller and larger-brained mammals. In mice, for example, they only undergo one round of cell division, but in humans they can divide multiple times and hence result in an increased number of neurons.

Although scientists were unclear of the mechanisms behind these differences, they suspected that a gene called Pax6 may play a key role, since its expression is elevated in human basal progenitors when compared with those of developing mice. To mimic this pattern, Max Planck scientists created a mouse line in which increased Pax6 expression was sustained.

To do this, the scientists introduced the Pax6 gene, In utero, into a type of progenitor cell called apical radial glia, which divides to both renew itself and generate basal progenitors. The result was a mouse line whereby Pax6 expression was prolonged exclusively in basal progenitors, or those committed to a neurogenic lineage. This differs from previous attempts, Huttner tells IFLScience, in which Pax6 overexpression did not distinguish between the right or the wrong cells, and was thus not limited to target populations of cells.

“There is no single Pax6 study that is that precisely reproducing the primate situation,” he added. “That’s pretty gratifying.”

As described in PLOS Biology, instead of undergoing the usual single round of cell division, the basal progenitors underwent multiple rounds of mitosis, “much like what we see in primate brains and humans,” lead author Fong Kuan Wong told IFLScience. “Because of this small difference it increased the neurons produced.” Notably, the researchers observed more neurons in the upper layer of the cortex, another pattern reminiscent of what we see in primates. Although the researchers didn’t specifically measure brain size, Wong says they would expect this to cause an increase in cortical thickness.

An interesting way to progress this research would be to see if this altered Pax6 expression induced behavioral changes, but for now the team is more interested in investigating how this gene is differentially regulated between species, Wong says. 

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