Scientists have discovered a key protein responsible for brain asymmetry

The genetic mechanisms underlying the brain's unique left-right differences are now better understood through new research, paving the way for a better understanding of human disorders associated with brain asymmetry.

A protein called Cachd1 plays a key role in establishing the different neural structure and function of each side of the brain, researchers from UCL, the Wellcome Sanger Institute, the University of Oxford and other collaborators have found. The study was published in Science.

By conducting genetic experiments on zebrafish, researchers discovered that when the Cachd1 mutation occurs, the right side of the brain loses its normal asymmetric development and becomes a mirror image of the left side. This disorder causes abnormal neural connections that affect brain function.

This discovery sheds light on the genetic mechanisms underlying brain asymmetry, a phenomenon observed in many animal species, including humans. Understanding these processes may lead to a better understanding of human disorders in which brain asymmetry is disrupted, such as schizophrenia, Alzheimer's disease, and autism spectrum disorders.

Despite their mirror anatomy, the left and right hemispheres of the human brain have functional differences that affect neural connections and cognitive processes such as language. How these left-right differences in neural circuitry arise is still poorly understood.

Using zebrafish—a well-known model organism for studying brain development thanks to their transparent embryos—the researchers set out to study how Cachd1 might influence brain asymmetry.

The team found that when Cachd1 is mutated, a region of the brain called the habenula loses its normal left-right distinction. Neurons on the right side become similar to neurons on the left side, disrupting neural connections in the habenula and potentially affecting its function.

Knockdown of cachd1 using morpholinos results in bilateral symmetry. (A-B) Dorsal view at 4 days postfertilization of uninjected wild types and cachd1 morpholino-injected larvae after whole-mount in situ hybridization using antisense riboprobes against asymmetric dorsal habenula markers kctd12.1. (C) Semiquantitative RT-PCR for cachd1 transcripts. Source: Science (2024). DOI: 10.1126/science.ade6970

Protein binding experiments have shown that Cachd1 binds to two receptors that allow cells to communicate through the Wnt signaling pathway, one of the most intensively studied cell communication pathways that plays important roles in early development, stem cell formation and many diseases. p>

In addition, the influence of Cachd1 appears to be specific to the right side of the brain, suggesting the presence of an unknown inhibitory factor limiting its activity on the left side. Although the full details have not yet been elucidated, evidence strongly suggests that Cachd1 plays a key role in establishing the distinction between the left and right sides of the developing brain by regulating cellular communication specifically on the right side.

Future studies will examine whether Cachd1 has other important functions associated with the Wnt pathway.

“This was a highly collaborative project that benefited greatly from an interdisciplinary approach—genetics, biochemistry, and structural biology came together to better understand the establishment of left-right asymmetry in the brain, as well as identify a new component of an important signaling pathway with multiple roles in health and disease,” says Dr Gareth Powell, co-author of the study, a former doctoral student at the Wellcome Sanger Institute and now a member of UCL's Department of Cell and Developmental Biology.

“I am pleased to see the publication of this highly collaborative research, which brought together many talented people with different scientific interests and skills from different institutions. Together, the team has enabled us to make exciting new discoveries in both the Wnt signaling pathway and the development of brain asymmetry,” says Professor Steve Wilson, senior author of the study from UCL's Department of Cell and Developmental Biology.