Drosophila circadian rhythm

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Front view of D. melanogaster showing the head and eyes. Drosophila melanogaster - front (aka).jpg
Front view of D. melanogaster showing the head and eyes.

Drosophila circadian rhythm is a daily 24-hour cycle of rest and activity in the fruit flies of the genus Drosophila . The biological process was discovered and is best understood in the species Drosophila melanogaster . Many behaviors are under circadian control including eclosion, locomotor activity, feeding, and mating. Locomotor activity is maximum at dawn and dusk, while eclosion is at dawn. [1]

Contents

Biological rhythms were first studied in Drosophila pseudoobscura . Drosophila circadian rhythm have paved the way for understanding circadian behaviour and diseases related to sleep-wake conditions in other animals, including humans. This is because the circadian clocks are fundamentally similar. [2] Drosophila circadian rhythm was discovered in 1935 by German zoologists, Hans Kalmus and Erwin Bünning. American biologist Colin S. Pittendrigh provided an important experiment in 1954, which established that circadian rhythm is driven by a biological clock. The genetics was first understood in 1971, when Seymour Benzer and Ronald J. Konopka reported that mutation in specific genes changes or stops the circadian behaviour. They discovered the gene called period (per), mutations of which alter the circadian rhythm. It was the first gene known to control behaviour. After a decade, Konopka, Jeffrey C. Hall, Michael Rosbash, and Michael W. Young discovered novel genes including timeless (tim), Clock (Clk), cycle (cyc), cry . These genes and their product proteins play a key role in the circadian clock. The research conducted in Benzer's lab is narrated in Time, Love, Memory by Jonathan Weiner.

For their contributions, Hall, Rosbash and Young received the Nobel Prize in Physiology or Medicine in 2017. [3]

History

During the process of eclosion by which an adult fly emerges from the pupa, Drosophila exhibits regular locomotor activity (by vibration) that occurs during 8-10 hours intervals starting just before dawn. The existence of this circadian rhythm was independently discovered in D. melanogaster in 1935 by two German zoologists, Hans Kalmus at the Zoological Institute of the German University in Prague (now Charles University), and Erwin Bünning at the Botanical Institute of the University of Jena. [4] [5] Kalmus discovered in 1938 that the brain area is responsible for the circadian activity. [6] Kalmus and Bünning were of the opinion that temperature was the main factor. But it was soon realized that even in different temperature, the circadian rhythm could be unchanged. [7] In 1954, Colin S. Pittendrigh at the Princeton University discovered the importance of light-dark conditions in D. pseudoobscura . He demonstrated that eclosion rhythm was delayed but not stopped when temperature was decreased. He concluded that temperature influenced only the peak hour of the rhythm, and was not the principal factor. [8] It was then known that the circadian rhythm was controlled by a biological clock. But the nature of the clock was then a mystery. [5]

After almost two decades, the existence of the circadian clock was discovered by Seymour Benzer and his student Ronald J. Konopka at the California Institute of Technology. They discovered that mutations in the X chromosome of D. melanogaster could make abnormal circadian activities. When a specific part of the chromosome was absent (inactivated), there was no circadian rhythm; in one mutation (called perS, "S" for short or shortened) the rhythm was shortened to ~19 hours; whereas, in another mutation (perL, "L" for long or lengthened) the rhythm was extended to ~29 hours, as opposed to a normal 24 hour rhythm. They published the discovery in 1971. [9] They named the gene location (locus) as period (per for short) as it controls the period of the rhythm. In opposition, there were other scientists that stated genes could not control such complex behaviors as circadian activities. [10]

Another circadian behavior in Drosophila is courtship between the male and female during mating. Courtship involves a song accompanied by a ritual locomotory dance in males. The main flight activity generally takes place in the morning and another peak occurs before sunset. Courtship song is produced by the male's wing vibration and consists of pulses of tone produced at intervals of approximately 34 msec in D. melanogaster (48 msec in D. simulans ). In 1980, Jeffrey C. Hall and his student Charalambos P. Kyriacou, at Brandeis University in Waltham, discovered that courtship activity is also controlled by per gene. [11] In 1984, Konopka, Hall, Michael Roshbash and their team reported in two papers that per locus is the centre of the circadian rhythm, and that loss of per stops circadian activity. [12] [13] At the same time, Michael W. Young's team at the Rockefeller University reported similar effects of per, and that the gene covers 7.1-kilobase (kb) interval on the X chromosome and encodes a 4.5-kb poly(A)+ RNA. [14] [15] In 1986, they sequenced the entire DNA fragment and found the gene encodes the 4.5-kb RNA, which produces a protein, a proteoglycan, composed of 1,127 amino acids. [16] At the same time Roshbash's team showed that PER protein is absent in mutant per. [17] In 1994, Young and his team discovered the gene timeless (tim) that influences the activity of per. [18] In 1998, they discovered doubletime (dbt), which regulate the amount of PER protein. [19]

In 1990, Konopka, Rosbash, and identified a new gene called Clock (Clk), which is vital for the circadian period. [20] In 1998, they found a new gene cycle (cyc), which act together with Clk. [21] In the late 1998, Hall and Roshbash's team discovered cryb , a gene for sensitivity to blue light. [22] They simultaneously identified the protein CRY as the main light-sensitive (photoreceptor) system. The activity of cry is under circadian regulation, and influenced by other genes such as per, tim, clk, and cyc. [23] The gene product CRY is a major photoreceptor protein belonging to a class of flavoproteins called cryptochromes. They are also present in bacteria and plants. [24] In 1998, Hall and Jae H. Park isolated a gene encoding a neuropeptide named pigment dispersing factor (PDF), based on one of the roles it plays in crustaceans. [25] In 1999, they discovered that pdf is expressed by lateral neurone ventral clusters (LNv) indicating that PDF protein is the major circadian neurotransmitter and that the LNv neurones are the principal circadian pacemakers. [26] In 2001, Young and his team demonstrated that glycogen synthase kinase-3 (GSK-3) ortholog shaggy (SGG) is an enzyme that regulates TIM maturation and accumulation in the early night, by causing phosphorylation. [27]

Hall, Rosbash and Young shared the Nobel Prize in Physiology or Medicine 2017 “for their discoveries of molecular mechanisms controlling the circadian rhythm”. [3]

Mechanism

Key centers of the mammalian and Drosophila brains (A) and the circadian system in Drosophila (B). Drosophila brains and the circadian system.jpg
Key centers of the mammalian and Drosophila brains (A) and the circadian system in Drosophila (B).

In Drosophila there are two distinct groups of circadian clocks, namely the clock neurones and the clock genes. They act concertedly to produce the 24-hour cycle of rest and activity. Light is the source of activation of the clocks. The compound eyes, ocelli, and Hofbauer-Buchner eyelets (HB eyelets) are the direct external photoreceptor organs. But the circadian clock can work in constant darkness. [28] Nonetheless, the photoreceptors are required for measuring the day length and detecting moonlight. The compound eyes are important for differentiating long days from constant light, and for the normal masking effects of light, such as inducing activity by light and inhibition by darkness. [29] There are two distinct activity peaks termed the M (for morning) peak, happening at dawn, and E (for evening) peak, at dusk. They monitor the different day lengths in different seasons of the year. [30] The light-sensitive proteins in the eye called, rhodopsins (rhodopsin 1 and 6), are crucial in activating the M and E oscillations. [31] When environmental light is detected, approximately 150 neurones (there are about 100,000 neurones in the Drosophila brain) in the brain regulate the circadian rhythm. [32] The clock neurones are located in distinct clusters in the central brain. The best-understood clock neurones are the large and small lateral ventral neurons (l-LNvs and s-LNvs) at the base of the optic lobe. These neurones produce pigment dispersing factor (PDF), a neuropeptide that acts as a circadian neuromodulator between different clock neurones. [33]

Molecular interactions of clock genes and proteins during Drosophila circadian rhythm. Drosophila circadian rhythm.jpg
Molecular interactions of clock genes and proteins during Drosophila circadian rhythm.

Drosophila circadian keeps time via daily fluctuations of clock-related proteins which interact in what is called a transcription-translation feedback loop. The core clock mechanism consists of two interdependent feedback loops, namely the PER/TIM loop and the CLK/CYC loop. [34] The CLK/CYC loop occurs during the day in which both Clock protein and cycle protein are produced. CLK/CYC heterodimer act as transcription factors and bind together to initiate the transcription of the per and tim genes by binding to a promoter element called E box, around mid-day. DNA is transcribed to produce PER mRNA and TIM mRNA. PER and TIM proteins are synthesized in the cytoplasm, and exhibit a smooth increase in levels over the course of the day. Their RNA levels peak early in the evening and protein levels peak around daybreak. [32] But their proteins levels are maintained at constantly low level until dusk, because during daylight also activates the doubletime (dbt) gene. DBT protein induces post-translational modifications, that is phosphorylation and turnover of monomeric PER proteins. As PER is translated in the cytoplasm, it is actively phosphorylated by DBT (casein kinase 1ε) and casein kinase 2 (synthesised by And and Tik) as a prelude to premature degradation. The actual degradation is through the ubiquitin-proteasome pathway, and is carried out by a ubiquitin ligase called Slimb (supernumery limbs). [35] [36] At the same time, TIM is itself phosphorylated by shaggy, whose activity declines after sunset. DBT gradually disappears, and withdrawal of DBT promotes PER molecules to get stabilized by physical association with TIM. Hence, maximum production of PER and TIM occurs at dusk. At the same time, CLK/CYC also directly activates vri and Pdp1 (the gene for PAR domain protein 1). VRI accumulates first, 3-6 hour earlier, and start to repress Clk; but the incoming of PDP1 creates a competition by activating Clk. PER/TIM dimer accumulate in the early night and translocate in an orchestrated fashion into the nucleus several hours later, and binds to CLK/CYC dimers. Bound PER completely stops the transcriptional activity of CLK and CYC. [37]

In the early morning, the appearance of light causes PER and TIM proteins to breakdown in a network of transcriptional activation and repression. First, light activates the cry gene in the clock neurones. Although CRY is produced deep inside the brain, it is sensitive to UV and blue light, and thus it easily signals the brain cells the onset of light. It irreversibly and directly binds to TIM causing it to break down through proteosome-dependent ubiquitin-mediated degradation. The CRY's photolyase homology domain is used for light detection and phototransduction, whereas the carboxyl-terminal domain regulates CRY stability, CRY-TIM interaction, and circadian photosensitivity. [38] The ubiquitination and subsequent degradation are aided by a different protein JET. [39] Thus PER/TIM dimer dissociates, and the unbound PER becomes unstable. PER undergoes progressive phosphorylation and ultimately degradation. Absence of PER and TIM allows activation of clk and cyc genes. Thus, the clock is reset to commence the next circadian cycle. [10]

Related Research Articles

<span class="mw-page-title-main">Circadian rhythm</span> Natural internal process that regulates the sleep-wake cycle

A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximise the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.

<span class="mw-page-title-main">Cryptochrome</span> Class of photoreceptors in plants and animals

Cryptochromes are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the chromatic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">PAS domain</span> Protein domain

A Per-Arnt-Sim (PAS) domain is a protein domain found in all kingdoms of life. Generally, the PAS domain acts as a molecular sensor, whereby small molecules and other proteins associate via binding of the PAS domain. Due to this sensing capability, the PAS domain has been shown as the key structural motif involved in protein-protein interactions of the circadian clock, and it is also a common motif found in signaling proteins, where it functions as a signaling sensor.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

Ronald J. Konopka (1947-2015) was an American geneticist who studied chronobiology. He made his most notable contribution to the field while working with Drosophila in the lab of Seymour Benzer at the California Institute of Technology. During this work, Konopka discovered the period (per) gene, which controls the period of circadian rhythms.

<i>Cycle</i> (gene)

Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include ARNTL and ARNTL2.

Doubletime (DBT), also known as discs overgrown (DCO), is a gene that encodes the doubletime protein in fruit flies. Michael Young and his team at Rockefeller University first identified and characterized the gene in 1998.

<span class="mw-page-title-main">Michael Rosbash</span> American geneticist and chronobiologist (born 1944)

Michael Morris Rosbash is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the Drosophila period gene in 1984 and proposed the Transcription Translation Negative Feedback Loop for circadian clocks in 1990. In 1998, they discovered the cycle gene, clock gene, and cryptochrome photoreceptor in Drosophila through the use of forward genetics, by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to the National Academy of Sciences in 2003. Along with Michael W. Young and Jeffrey C. Hall, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm".

<span class="mw-page-title-main">Jeffrey C. Hall</span> American geneticist and chronobiologist (born 1945)

Jeffrey Connor Hall is an American geneticist and chronobiologist. Hall is Professor Emeritus of Biology at Brandeis University and currently resides in Cambridge, Maine.

<span class="mw-page-title-main">Michael W. Young</span> American biologist and geneticist (born 1949)

Michael Warren Young is an American biologist and geneticist. He has dedicated over three decades to research studying genetically controlled patterns of sleep and wakefulness within Drosophila melanogaster.

Paul H. Taghert is an American chronobiologist known for pioneering research on the roles and regulation of neuropeptide signaling in the brain using Drosophila melanogaster as a model. He is a professor of neuroscience in the Department of Neuroscience at Washington University in St. Louis.

Jeffrey L. Price is an American researcher and author in the fields of circadian rhythms and molecular biology. His chronobiology work with Drosophila melanogaster has led to the discoveries of the circadian genes timeless (tim) and doubletime (dbt), and the doubletime regulators spaghetti (SPAG) and bride of doubletime (BDBT).

Paul Hardin is an American scientist in the field of chronobiology and a pioneering researcher in the understanding of circadian clocks in flies and mammals. Hardin currently serves as a distinguished professor in the biology department at Texas A&M University. He is best known for his discovery of circadian oscillations in the mRNA of the clock gene Period (per), the importance of the E-Box in per activation, the interlocked feedback loops that control rhythms in activator gene transcription, and the circadian regulation of olfaction in Drosophila melanogaster. Born in a suburb of Chicago, Matteson, Illinois, Hardin currently resides in College Station, Texas, with his wife and three children.

Vrille (vri) is a bZIP transcription factor found on chromosome 2 in Drosophila melanogaster. Vrille mRNA and protein product (VRI) oscillate predictably on a 24-hour timescale and interact with other circadian clock genes to regulate circadian rhythms in Drosophila. It is also a regulator in embryogenesis; it is expressed in multiple cell types during multiple stages in development, coordinating embryonic dorsal/ventral polarity, wing-vein differentiation, and ensuring tracheal integrity. It is also active in the embryonic gut but the precise function there is unknown. Mutations in vri alter circadian period and cause circadian arrhythmicity and developmental defects in Drosophila.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

dClock (clk) is a gene located on the 3L chromosome of Drosophila melanogaster. Mapping and cloning of the gene indicates that it is the Drosophila homolog of the mouse gene CLOCK (mClock). The Jrk mutation disrupts the transcription cycling of per and tim and manifests dominant effects.

Ravi Allada is an Indian-American chronobiologist studying the circadian and homeostatic regulation of sleep primarily in the fruit fly Drosophila. He is currently the Executive Director of the Michigan Neuroscience Institute (MNI), a collective which connects neuroscience investigators across the University of Michigan to probe the mysteries of the brain on a cellular, molecular, and behavioral level. Working with Michael Rosbash, he positionally cloned the Drosophila Clock gene. In his laboratory at Northwestern, he discovered a conserved mechanism for circadian control of sleep-wake cycle, as well as circuit mechanisms that manage levels of sleep.

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