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Biological Chemistry

How evolution repurposed a bone gene for brain development

Study suggests gene that mice express in muscle and bone helps regulate how primate neurons form connections

by Michael Torrice
November 10, 2016 | A version of this story appeared in Volume 94, Issue 45

Micrographs of cultured human neurons.
Credit: Nature
Cultured human neurons (left) show increased dendrite growth (right) when OSTN expression is decreased.

Millions of years of evolution separate us from our last common ancestor with mice. In that time, our brains, and those of other primates, have picked up some impressive cognitive abilities.

A team of neurobiologists now report an example of genetic tinkering that helped this happen. They found that a handful of DNA base pair changes allowed a gene normally expressed in the muscle and bone of mice to turn on in primate brains when neurons fire (Nature 2016, DOI: 10.1038/nature20111). Because this gene gets expressed in response to brain activity, the researchers think that it plays a role in how our brains develop during childhood as we process inputs from the world around us.

The work “gets at this underlying question of how did we as a species, and primates more generally, evolve our cognitive abilities,” says Justine Kupferman of Columbia University, who, along with Franck Polleux, wrote a perspective accompanying the new report.

The research team, including Bulent Ataman, Gabriella L. Boulting, and Michael E. Greenberg of Harvard Medical School, pinpointed this gene by subjecting cultured human neurons to conditions that mimic what happens when neurons receive input from other cells in the brain. One gene active in human cells but not in mouse cells was OSTN, which codes for the protein osteocrin.

Further experiments revealed that, when turned on in neurons, OSTN helps regulate the growth and shape of dendrites, the spiny structures the cells use to connect up with their neighbors during development and learning and memory.

The Harvard team also found changes, which had accumulated over evolutionary time, to DNA sequences that regulate OSTN expression. These changes allowed for a transcription factor to turn on the gene when neurons become active, explaining why the gene is expressed in primate but not mouse brains.

Besides beginning to paint a picture of how primate brains developed such complexity, Boulting says the findings point out there can be profound differences between how human and mouse neurons behave, suggesting researchers should think past mouse models of what happens in our brains.

“There’s much more work to be done on characterizing what the gene does during brain development or during circuit development,” Polleux says. “The work raises more questions than it answers, but that’s the whole idea behind good research.”



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