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1. The Drosophila circadian clock gene cycle controls the development of clock neurons

   https://doi.org/10.1371/journal.pgen.1011441  

   Biondi, Grace; McCormick, Gina; Fernandez, Maria P (October 2024, PLOS Genetics)

   Ewer, John (Ed.)

   Daily behavioral and physiological rhythms are controlled by the brain’s circadian timekeeping system, a synchronized network of neurons that maintains endogenous molecular oscillations. These oscillations are based on transcriptional feedback loops of clock genes, which inDrosophilainclude the transcriptional activatorsClock (Clk)andcycle (cyc). While the mechanisms underlying this molecular clock are very well characterized, the roles that the core clock genes play in neuronal physiology and development are much less understood. TheDrosophilatimekeeping center is composed of ~150 clock neurons, among which the four small ventral lateral neurons (sLN_vs) are the most dominant pacemakers under constant conditions. Here, we show that downregulating the clock genecycspecifically in thePdf-expressing neurons leads to decreased fasciculation both in larval and adult brains. This effect is due to a developmental role ofcyc, as both knocking downcycor expressing a dominant negative form ofcycexclusively during development lead to defasciculation phenotypes in adult clock neurons.Clkdownregulation also leads to developmental effects on sLNv morphology. Our results reveal a non-circadian role forcyc, shedding light on the additional functions of circadian clock genes in the development of the nervous system. 

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2. Overlapping Central Clock Network Circuitry Regulates Circadian Feeding and Activity Rhythms in Drosophila

   https://doi.org/10.1177/07487304241263734  

   Saurabh, Sumit; Meier, Ruth_J; Pireva, Liliya_M; Mirza, Rabab_A; Cavanaugh, Daniel_J (July 2024, Journal of Biological Rhythms)

   The circadian system coordinates multiple behavioral outputs to ensure proper temporal organization. Timing information underlying circadian regulation of behavior depends on a molecular circadian clock that operates within clock neurons in the brain. In Drosophila and other organisms, clock neurons can be divided into several molecularly and functionally discrete subpopulations that form an interconnected central clock network. It is unknown how circadian signals are coherently generated by the clock network and transmitted across output circuits that connect clock cells to downstream neurons that regulate behavior. Here, we have exhaustively investigated the contribution of clock neuron subsets to the control of two prominent behavioral outputs in Drosophila: locomotor activity and feeding. We have used cell-specific manipulations to eliminate molecular clock function or induce electrical silencing either broadly throughout the clock network or in specific subpopulations. We find that clock cell manipulations produce similar changes in locomotor activity and feeding, suggesting that overlapping central clock circuitry regulates these distinct behavioral outputs. Interestingly, the magnitude and nature of the effects depend on the clock subset targeted. Lateral clock neuron manipulations profoundly degrade the rhythmicity of feeding and activity. In contrast, dorsal clock neuron manipulations only subtly affect rhythmicity but produce pronounced changes in the distribution of activity and feeding across the day. These experiments expand our knowledge of clock regulation of activity rhythms and offer the first extensive characterization of central clock control of feeding rhythms. Despite similar effects of central clock cell disruptions on activity and feeding, we find that manipulations that prevent functional signaling in an identified output circuit preferentially degrade locomotor activity rhythms, leaving feeding rhythms relatively intact. This demonstrates that activity and feeding are indeed dissociable behaviors, and furthermore suggests that differential circadian control of these behaviors diverges in output circuits downstream of the clock network. 

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3. Neonicotinoids disrupt circadian rhythms and sleep in honey bees

   https://doi.org/10.1038/s41598-020-72041-3  

   Tackenberg, Michael C.; Giannoni-Guzmán, Manuel A.; Sanchez-Perez, Erik; Doll, Caleb A.; Agosto-Rivera, José L.; Broadie, Kendal; Moore, Darrell; McMahon, Douglas G. (December 2020, Scientific Reports)

   Abstract Honey bees are critical pollinators in ecosystems and agriculture, but their numbers have significantly declined. Declines in pollinator populations are thought to be due to multiple factors including habitat loss, climate change, increased vulnerability to disease and parasites, and pesticide use. Neonicotinoid pesticides are agonists of insect nicotinic cholinergic receptors, and sub-lethal exposures are linked to reduced honey bee hive survival. Honey bees are highly dependent on circadian clocks to regulate critical behaviors, such as foraging orientation and navigation, time-memory for food sources, sleep, and learning/memory processes. Because circadian clock neurons in insects receive light input through cholinergic signaling we tested for effects of neonicotinoids on honey bee circadian rhythms and sleep. Neonicotinoid ingestion by feeding over several days results in neonicotinoid accumulation in the bee brain, disrupts circadian rhythmicity in many individual bees, shifts the timing of behavioral circadian rhythms in bees that remain rhythmic, and impairs sleep. Neonicotinoids and light input act synergistically to disrupt bee circadian behavior, and neonicotinoids directly stimulate wake-promoting clock neurons in the fruit fly brain. Neonicotinoids disrupt honey bee circadian rhythms and sleep, likely by aberrant stimulation of clock neurons, to potentially impair honey bee navigation, time-memory, and social communication. 

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4. The E3 Ligases Spsb1 and Spsb4 Regulate RevErbα Degradation and Circadian Period

   https://doi.org/10.1177/0748730419878036  

   Mekbib, Tsedey; Suen, Ting-Chung; Rollins-Hairston, Aisha; DeBruyne, Jason_P (October 2019, Journal of Biological Rhythms)

   The time-dependent degradation of core circadian clock proteins is essential for the proper functioning of circadian timekeeping mechanisms that drive daily rhythms in gene expression and, ultimately, an organism’s physiology. The ubiquitin proteasome system plays a critical role in regulating the stability of most proteins, including the core clock components. Our laboratory developed a cell-based functional screen to identify ubiquitin ligases that degrade any protein of interest and have started screening for those ligases that degrade circadian clock proteins. This screen identified Spsb4 as a putative novel E3 ligase for RevErbα. In this article, we further investigate the role of Spsb4 and its paralogs in RevErbα stability and circadian rhythmicity. Our results indicate that the paralogs Spsb1 and Spsb4, but not Spsb2 and Spsb3, can interact with and facilitate RevErbα ubiquitination and degradation and regulate circadian clock periodicity. 

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5. Circadian Interactomics: How Research Into Protein-Protein Interactions Beyond the Core Clock Has Influenced the Model of Circadian Timekeeping

   https://doi.org/10.1177/07487304211014622  

   Mosier, Alexander_E; Hurley, Jennifer_M (May 2021, Journal of Biological Rhythms)

   The circadian clock is the broadly conserved, protein-based, timekeeping mechanism that synchronizes biology to the Earth’s 24-h light-dark cycle. Studies of the mechanisms of circadian timekeeping have placed great focus on the role that individual protein-protein interactions play in the creation of the timekeeping loop. However, research has shown that clock proteins most commonly act as part of large macromolecular protein complexes to facilitate circadian control over physiology. The formation of these complexes has led to the large-scale study of the proteins that comprise these complexes, termed here “circadian interactomics.” Circadian interactomic studies of the macromolecular protein complexes that comprise the circadian clock have uncovered many basic principles of circadian timekeeping as well as mechanisms of circadian control over cellular physiology. In this review, we examine the wealth of knowledge accumulated using circadian interactomics approaches to investigate the macromolecular complexes of the core circadian clock, including insights into the core mechanisms that impart circadian timing and the clock’s regulation of many physiological processes. We examine data acquired from the investigation of the macromolecular complexes centered on both the activating and repressing arm of the circadian clock and from many circadian model organisms. 

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