An Abnormal Connection

Strabismus is just one of the conditions caused by abnormalities in the cranial neuromuscular system. Despite affecting four percent of the US population (1), tissue inaccessibility has left it, and other brain-muscle conditions, relatively unexplored. It’s why a team at the National Institute of Genetics in Japan has turned to zebrafish to help understand genetic mutations that might be driving the condition.

“Strabismus is one of the conditions where brain and muscle connections can be abnormal. The connection between abducens motor neurons and their target muscle – the lateral rectus – is an excellent model to study the basic principle of brain-muscle connections,” explains Kazuhide Asakawa, who led the associated  study (2). “As neurons in the abducens nucleus connect only with lateral rectus, and the sole behavioral role is to generate outward eye movements, this allows us to evaluate the effects of a genetic mutation at the molecular, cellular and behavioral level.” Their target? Protocadherin – a protein expressed in abducens motor neurons that the team hypothesized might play a key role in axon growth.

Using CRISPR-Cas9, the team induced mutations in pcdh17 – the gene encoding for protocadherin. “The changes that occurred were striking,” says Asakawa. “When mutant Pcdh17 was expressed, the abducens motor neurons formed cellular aggregates, and failed to position properly in the brain and extend axons toward the eye globe. This led us to believe that abducens motor neurons actually repel each other.” He adds: “This was somewhat counterintuitive to us because neurons with similar functions usually cluster together, making it difficult for us to imagine repulsive force operating in between.”

According to Asakawa, their findings have uncovered the importance of protocadherins in connecting the abducens nucleus to the lateral rectus muscle – the brain and eye muscle, respectively. “The involvement of protocadherins in strabismus has not been established yet in humans, but we hope our work in zebrafish contributes to help estimate the risk of developing strabismus, and increase the chances of initiating early treatment to prevent impaired eye movement.” Outside the realm of ophthalmology, Asakawa and his team hope to explore how protocadherins contribute towards connecting other neurons and muscle fibers. “Some connections in the brain and eye are selectively resistant to degeneration. We hope our work can go some way in contributing towards the protection of motor neurons in fatal diseases such as ALS.”