Proteins are essential building blocks of our bodies—they help cells grow, send signals, and carry out countless functions. In the brain, certain proteins are especially important for guiding how the brain develops and works. Sometimes, these proteins work in teams by physically connecting with one another.

This article focuses on two such proteins: ataxin-1 (ATXN1) and capicua (CIC). These two proteins form a team—or “complex”—that plays a key role in brain development. When everything works normally, the ATXN1-CIC complex helps brain cells grow and function properly.

But what happens when this complex doesn’t work the way it should?

Some diseases, like spinocerebellar ataxia type 1 (SCA1)—a rare adult-onset condition that affects movement—occur when mutations cause this protein complex to work too well. This is known as a “gain-of-function” mutation. It’s like having a machine that works in overdrive and ends up damaging the system.

On the flip side, other mutations cause a “loss-of-function.” This means the proteins stop working properly, either because they’re missing completely, only partly made, or made in a broken form. In this study, researchers wanted to know: What happens in the developing brain when the ATXN1-CIC complex is lost?

To find out, the scientists studied developing mouse brains. First, they confirmed that the ATXN1-CIC complex is normally present during early brain development. Then, they removed this protein complex in young mice to see what would happen.

When the ATXN1-CIC protein complex was removed from the developing brain, scientists observed several problems. Most notably, a part of the brain called the cortex became smaller. The cortex is important for attention, thinking, memory, and other higher-level brain functions. This shrinkage was linked to the loss of brain cells (neurons) in that region.

Interestingly, the loss of neurons wasn’t widespread—it was limited to a specific part of the cortex. This finding showed that ATXN1-CIC is especially important for keeping certain neurons alive during brain development.

To understand how these brain changes affected behavior, the researchers performed a series of tests on the mice that lacked the ATXN1-CIC complex. These tests are designed to measure things like activity levels, learning and memory, and social interactions.

The results were striking. Mice without ATXN1-CIC in their brains were overactive and showed less anxiety than usual. They also struggled with tasks that tested their ability to remember places and contexts—suggesting problems with learning and memory. In addition, these mice showed more aggressive behavior and had difficulty with social interactions, showing traits that resemble some features of autism spectrum disorders.

To see if the findings in mice could help us understand human brain conditions, the researchers looked for people who had mutations in the CIC gene. Using DNA sequencing, they identified five individuals with changes in this gene.

All five people had a range of neurodevelopmental challenges, including:

Intellectual disability or developmental delays

Autism spectrum disorder

Attention deficit/hyperactivity disorder (ADHD)

Seizures

Further analysis showed that these mutations caused the body to produce only half the normal amount of CIC protein. As a result, the ATXN1-CIC complex couldn’t form or function properly—mirroring what was seen in the mice. This disruption likely contributed to abnormal brain development and the neurological symptoms observed in these individuals.

In summary, this study shows that the ATXN1-CIC complex, while already known to play a role in the adult brain disease spinocerebellar ataxia type 1 (SCA1), is also essential for healthy brain development in children. These findings not only highlight the importance of this protein complex in both early and later life, but also show how animal studies can help us better understand human brain development and uncover clues about developmental brain disorders. 

Reference:

Lu, H. C. et al. Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nature Genetics 49, 527-536, doi:10.1038/ng.3808 (2017). Link to the full text article.