Unlocking the brain's timekeepers: Clock genes

Our brains are primed to keep track of time with the natural rhythms of the day. That's thanks to our circadian clock.

This circadian system doesn’t just dictate our sleep-wake cycles; it controls a variety of behaviors and biological functions, from hormone release to body temperature.

The core of this system lies in specialized circadian genes that produce molecules that regulate daily rhythms. While the mechanisms of these genes have been studied for their role in managing time, their function in development has largely been a mystery.

A recent study with fruit flies unveils a new role for these genes beyond just timekeeping. It turns out our circadian genes may also play a critical part in shaping the brain’s development and structure.

The study.
Fruit flies are commonly used in studies on circadian rhythms because they share similar clock genes with mammals, such as a specific clock gene called cycle. This gene, together with another gene called clock, forms a loop that controls the production and decay of specific proteins every 24 hours.

In the fly’s brain, these rhythms are regulated by around 150 neurons that communicate based on their cycle and clock gene activities.

In the study, the scientists examined the action of the circadian cycle and clock genes in both larvae (baby flies) and adult flies. They did that by increasing and decreasing the activity of the two genes during brain development.

The researchers found that cycle and clock genes are not just setting daily rhythms but are also crucial for developing these neurons in the first place.

By downregulating the cycle gene in the developing fly, the study observed a significant reduction in the “bundling” of the 150 neurons, meaning the neurons didn’t bundle together as they should as the brain developed.

Bundling (also called fasciculation) is essential because it allows neuron pathways to form correctly, supporting healthy communication throughout the brain.

This change in structure happened even before the neurons established their timekeeping function, pointing to an unexpected role for these clock genes in neuron development.

When cycle expression was reduced in young, developing flies, it caused the neurons in adult flies to develop unstructured projections instead of the normal bundled and structured pathways. That disrupted both the normal pathway’s form and, ultimately, their function in circadian rhythm.

Likewise, changes to the clock gene produced similar but different developmental abnormalities, revealing unique contributions from each gene.

These findings are in line with similar observations in mammals. In mice, mutations in a cycle-related gene have been associated with memory issues, shortened lifespan, and faster brain aging. This hints that possibly in humans, too, genes previously thought to be involved only in our circadian rhythm may also play important roles in brain development and maintenance.

In conclusion
Clock genes like cycle and clock have surprising roles in neuron formation and structure, showing that they are not limited to managing daily biological rhythms. They may contribute to building the brain itself.

Researchers believe that these genes might influence factors like how nerve cells migrate during brain development or even the stability of the brain’s basic structure.

By studying these effects, we could better understand not only the basic biology of brain growth but also the origins of neurodevelopmental disorders that might relate to clock gene activity.

So perhaps, a well-functioning circadian system is linked to more than just good sleep.

About the scientific paper:

First author: Grace Biondi, USA
Published: PLOS. October 2024.
Link to paper: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1011441