OCT 03, 2021 3:27 AM PDT

A Tumor-Suppressor Gene Plays a Role in the Circadian Rhythm

WRITTEN BY: Carmen Leitch

Organisms follow the cycle of the day, even at the cellular level, creating an internal clock. Humans' biology will follow this circadian rhythm even when external stimuli like light or temperature changes don't occur. Researchers have now used a fruit fly model to identify a role for a gene called neurofibromin (NF1) in the regulation of the circadian rhythm. Mutations in Nf1 cause the disease neurofibromatosis, which leads to tumor growth in the nervous system. Sleep disturbances are also known to be a symptom of neurofibromatosis.

Image credit: Max Pixel

The circadian rhythm or sleep-wake cycle is involved in a variety of biological processes including the regulation of temperature, blood pressure and heart rate, hormone production, as well as cognition, memory, and mood. This cycle is why we tend to have a warmer internal temperature and not as many intestinal contractions at night.

In this work, which was reported in Nature Communicatons, the researchers used infrared sensors to monitor the movement of fruit flies kept in tubes. During a 24-hour period, the flies slept for about ten hours at night, and then remained active for the rest of the day, except for about a four- to five-hour nap.

A lot is known about the fruit fly model because of its extensive use in research, so scientists have revealed many aspects of fruit fly brain function. In this study, the scientists analyzed gene expression in neurons that are part of a region of the zebrafish brain that's involved in learning and sleep, known as mushroom bodies because of their shape. This was done for both healthy, normal fruit flies and flies with a dysregulated sleep-wake cycle.

"We identified a gene, Nf1, whose expression fluctuates according to the sleep-wake phases of the fly: its expression increases when the flies are awake, while it decreases during their sleep," said Blanca Lago Solis, researcher at the University of Geneva (UNIGE).

Following up on the Nf1 gene, the researchers determined that flies with chronically low Nf1 expression levels have aberrant sleep cycles. "These flies are totally dysregulated and have much more sleep phases," noted Lago Solis.

Neurons in the mushroom bodies are activated by calcium release, and the NF1 protein is known to be upstream of that process in flies. When the protein is expressed, neurons in the mushroom body are more active, promoting wakefulness during the daytime. The expression level is reduced at night.

In humans, the NF1 protein suppresses tumor growth in the nervous system (by regulating the activity of the p21 oncoprotein Ras). Mutations in the Nf1 gene cause neurofibromatosis, which can cause a range of symptoms that can include sleep disturbances; "...it will be interesting to explore the potential role of Nf1 in this phenomenon," said study leader Emi Nagoshi, a Professor at UNIGE.

Sources: University of Geneva, Nature Communications

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