June 5, 2018
by  | NIH

In seeking the biological answer to the question of what it means to be human, the brain’s cerebral cortex is a good place to start. This densely folded, outer layer of grey matter, which is vastly larger in Homo sapiens than in other primates, plays an essential role in human consciousness, language, and reasoning.

Now, an NIH-funded team has pinpointed a key set of genes—found only in humans—that may help explain why our species possesses such a large cerebral cortex. Experimental evidence shows these genes prolong the development of stem cells that generate neurons in the cerebral cortex, which in turn enables the human brain to produce more mature cortical neurons and, thus, build a bigger cerebral cortex than our fellow primates.

That sounds like a great advantage for humans! But there’s a downside. Researchers found the same genomic changes that facilitated the expansion of the human cortex may also render our species more susceptible to certain rare neurodevelopmental disorders.

This remarkable story of discovery began back in 2012 when Frank Jacobs, then a postdoctoral researcher working with David Haussler and Sofie Salama at the University of California, Santa Cruz, grew small patches of cerebral cortex in lab dishes. Jacobs coaxed radial glial stem cells from humans and rhesus macaques to differentiate into cortical neurons. Those cortical neurons went on to form multi-layered pieces of cortex, which they call cortical organoids. The goal was to examine gene activity within those developing organoids in search of notable differences between the brains of people and macaques.

An obvious place to look is the so-called Notch signaling genes, long known for their roles in brain development. Jacobs noticed that the Notch signal seemed to come on stronger and longer in human compared to macaque organoids in the first several weeks of development. Even more intriguing was a gene, called NOTCH2NL. While highly active in the developing human organoids, that gene was missing altogether in macaques.

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