A single gene helps regulate the sleep–wake cycle

All living organisms are subject to an internal biological rhythm, which controls many physiological processes. Using the genetic model organism Drosophila melanogaster (fruit fly), a team from the University of Geneva (UNIGE) has discovered that the Nf1 gene is essential for the regulation of the sleep–wake cycle. Their work has been published in the journal Nature Communications.

Most biological functions as well as certain cognitive abilities are regulated by the circadian rhythm, a 24-hour cycle; the internal clock, located in humans in the hypothalamus, that means we are most awake from morning until the end of the day, that our body temperature is significantly higher during the day and that intestinal contractions are lower at night. UNIGE researchers in the laboratory of Professor Emi Nagoshi are using Drosophila to study in detail the mechanisms that regulate these internal clocks. Not only can the fly and its genome be manipulated very easily in the laboratory, but many genes are conserved between the fly and higher organisms, which often makes it possible to extend the scope of discoveries from fruit flies to humans.

Using infrared sensors that detect the movements of flies contained in tubes, scientists can easily analyse their sleep–wake cycles. Over a 24-hour period, flies sleep for about 10 hours at night and then are active all day, except for a nap of 4–5 hours. The biologists were interested in flies that have a deregulated sleep–wake cycle and whose particular area of the brain, called ‘mushroom bodies’ because of its characteristic shape, is damaged. They analysed the expression of genes in this area of the brain of healthy Drosophila.

“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 UNIGE researcher Blanca Lago Solis.

To confirm the link between this gene and the circadian rhythm, the biologists observed flies that weakly express this gene, regardless of the time of day. “These flies are totally dysregulated and have much more sleep phases,” Lago Solis said.

The NF1 protein is upstream of a regulatory cascade that triggers the release of calcium, which is necessary for the activation of neurons in the brain’s mushroom bodies. The expression of Nf1 causes a higher activity of neurons in this area of the brain during the day than at night, thus promoting daytime wakefulness.

The human homolog of Nf1 is a gene that prevents the development of tumours in the nervous system. As noted by Prof Nagoshi, “When a person carries a mutation in the Nf1 gene, he or she has neurofibromatosis — a common genetic disease that predisposes to the development of nervous system tumours. One of the symptoms of patients with neurofibromatosis is sleep disturbance, and it will be interesting to explore the potential role of Nf1 in this phenomenon.”

Image caption: Neurons in the Drosophila brain marked with green fluorescent protein. The most coloured parts highlight the mushroom bodies, a key centre for sleep regulation. Image ©UNIGE

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