PDF Cycling in the Dorsal Protocerebrum of the Drosophila Brain Is Not Necessary for Circadian Clock Function
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Paul Hardin, Ph.D. John W
Department of Biology The College of Arts + Sciences | Indiana University Bloomington About Paul Hardin Distinguished Alumni Award Lecture Thu., Oct. 18, 2018 • 4 to 5 pm • Myers Hall 130 Paul Hardin, Ph.D. John W. Lyons Jr. ’59 Chair in Biology, Texas A&M University Genetic architecture underlying circadian clock initiation, maintenance, and output in Drosophila Circadian clocks drive daily rhythms in metabolism, physiology, and behavior in organisms ranging from cyanobacteria to humans. The identification and analysis of “clock genes” in Drosophila revealed that circadian timekeeping is based on a transcriptional feedback loop Paul Hardin studied the development of the sea in which CLOCK-CYCLE (CLK-CYC) heterodimers activate transcription of their feedback urchin embryo in William Klein’s lab at Indiana repressors PERIOD (PER) and TIMELESS (TIM). Subsequent studies revealed that similar University, from where he received his Ph.D. in transcriptional feedback loops keep circadian time in all eukaryotes and, in the case of 1987. He did his postdoctoral fellowship with animals, that these feedback loops are comprised of conserved components. The “core” Michael Rosbash at Brandeis University, working feedback loop described above operates in conjunction with an “interlocked” feedback on the circadian rhythms of the fruit fly, Drosophila loop in animals to drive rhythmic transcription of hundreds of genes that are maximally melanogaster. His work with Michael Rosbash and expressed at different phases of the circadian cycle. These feedback loops operate in many, Jeff Hall has been instrumental to our understanding but not all, tissues in flies including the brain pacemaker neurons that control rest:activity of how circadian rhythms affect a myriad of rhythms. -
Regulation of Drosophila Circadian Rhythms by Mirna Let-7 Is Mediated by a Regulatory Cycle
ARTICLE Received 10 Jul 2014 | Accepted 10 Oct 2014 | Published 24 Nov 2014 DOI: 10.1038/ncomms6549 Regulation of Drosophila circadian rhythms by miRNA let-7 is mediated by a regulatory cycle Wenfeng Chen1,*, Zhenxing Liu1,*, Tianjiao Li1, Ruifeng Zhang1, Yongbo Xue1, Yang Zhong1, Weiwei Bai1, Dasen Zhou1 & Zhangwu Zhao1 MicroRNA-mediated post-transcriptional regulations are increasingly recognized as important components of the circadian rhythm. Here we identify microRNA let-7, part of the Drosophila let-7-Complex, as a regulator of circadian rhythms mediated by a circadian regulatory cycle. Overexpression of let-7 in clock neurons lengthens circadian period and its deletion attenuates the morning activity peak as well as molecular oscillation. Let-7 regulates the circadian rhythm via repression of CLOCKWORK ORANGE (CWO). Conversely, upregulated cwo in cwo-expressing cells can rescue the phenotype of let-7-Complex overexpression. Moreover, circadian prothoracicotropic hormone (PTTH) and CLOCK- regulated 20-OH ecdysteroid signalling contribute to the circadian expression of let-7 through the 20-OH ecdysteroid receptor. Thus, we find a regulatory cycle involving PTTH, a direct target of CLOCK, and PTTH-driven miRNA let-7. 1 Department of Entomology, College of Agronomy and Biotechnology, China Agricultural University, Beijing 100193, China. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to Z.Z. (email: [email protected]). NATURE COMMUNICATIONS | 5:5549 | DOI: 10.1038/ncomms6549 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms6549 lmost all animals display a wide range of circadian bantam-dependent regulation of Clk expression is required for rhythms in behaviour and physiology, such as locomotor circadian rhythm. -
Metabolic Inactivation of the Circadian Transmitter, Pigment Dispersing Factor (PDF), by Neprilysin-Like Peptidases in Drosophila R
4465 The Journal of Experimental Biology 210, 4465-4470 Published by The Company of Biologists 2007 doi:10.1242/jeb.012088 Metabolic inactivation of the circadian transmitter, pigment dispersing factor (PDF), by neprilysin-like peptidases in Drosophila R. Elwyn Isaac1,*, Erik C. Johnson2, Neil Audsley3 and Alan D. Shirras4 1Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK, 2Department of Biology, Wake Forest University, NC, USA, 3Central Science Laboratory, Sand Hutton, York, YO41 1LZ, UK and 4Department of Biological Sciences, University of Lancaster, LA1 4YQ, UK *Author for correspondence (e-mail: [email protected]) Accepted 4 October 2007 Summary Recent studies have firmly established pigment confirming that such cleavage results in PDF inactivation. dispersing factor (PDF), a C-terminally amidated The Ser7–Leu8 peptide bond was also the principal octodecapeptide, as a key neurotransmitter regulating cleavage site when PDF was incubated with membranes rhythmic circadian locomotory behaviours in adult prepared from heads of adult Drosophila. This Drosophila melanogaster. The mechanisms by which PDF endopeptidase activity was inhibited by the neprilysin –1 functions as a circadian peptide transmitter are not fully inhibitors phosphoramidon (IC50, 0.15·mol·l ) and –1 understood, however; in particular, nothing is known thiorphan (IC50, 1.2·mol·l ). We propose that cleavage by about the role of extracellular peptidases in terminating a member of the Drosophila neprilysin family of PDF signalling at synapses. In this study we show that PDF endopeptidases is the most likely mechanism for is susceptible to hydrolysis by neprilysin, an endopeptidase inactivating synaptic PDF and that neprilysin might have that is enriched in synaptic membranes of mammals and an important role in regulating PDF signals within insects. -
Pololu Jrk USB Motor Controller User's Guide
Pololu Jrk USB Motor Controller User’s Guide © 2001–2019 Pololu Corporation Pololu Jrk USB Motor Controller User’s Guide https://www.pololu.com/docs/0J38/all Page 1 of 55 Pololu Jrk USB Motor Controller User’s Guide © 2001–2019 Pololu Corporation 1. Overview . 3 1.a. Module Pinout and Components . 6 1.b. Supported Operating Systems . 9 1.c. PID Calculation Overview . 10 2. Contacting Pololu . 12 3. Configuring the Motor Controller . 13 3.a. Installing Windows Drivers and the Configuration Utility . 13 3.b. Input Options . 18 3.c. Feedback Options . 20 3.d. PID Options . 22 3.e. Motor Options . 24 3.f. Error Response Options . 27 3.g. The Plots Window . 29 3.h. Upgrading Firmware . 30 4. Using the Serial Interface . 33 4.a. Serial Modes . 33 4.b. TTL Serial . 34 4.c. Command Protocols . 36 4.d. Cyclic Redundancy Check (CRC) Error Detection . 37 4.e. Motor Control Commands . 39 4.f. Error Reporting Commands . 41 4.g. Variable Reading Commands . 44 4.h. Daisy-Chaining . 46 4.i. Serial Example Code . 48 4.i.1. Cross-platform C . 48 4.i.2. Windows C . 50 5. Setting Up Your System . 51 6. Writing PC Software to Control the Jrk . 55 Page 2 of 55 Pololu Jrk USB Motor Controller User’s Guide © 2001–2019 Pololu Corporation 1. Overview The jrk family of versatile, general-purpose motor controllers supports a variety of interfaces, including USB. Analog voltage and tachometer (frequency) feedback options allow quick implementation of closed-loop servo systems, and a free configuration utility (for Windows) allows easy calibration and configuration through the USB port. -
A Mutant Drosophila Homolog of Mammalian Clock Disrupts
Cell, Vol. 93, 791±804, May 29, 1998, Copyright 1998 by Cell Press AMutantDrosophila Homolog of Mammalian Clock Disrupts Circadian Rhythms and Transcription of period and timeless Ravi Allada,*²³§ Neal E. White,³ Aronson et al., 1994; Shearman et al., 1997; Sun et al., W. Venus So,²³ Jeffrey C. Hall,²³ 1997; Tei et al., 1997). ²³ and Michael Rosbash* k In Drosophila, there are two well-characterized clock *Howard Hughes Medical Institute genes: period (per) and timeless (tim). Protein levels, ² NSF, Center for Biological Timing RNA levels, and transcription rates of these two genes ³ Department of Biology undergo robust circadian oscillations (Zerr et al., 1990; Brandeis University Hardin et al., 1990, 1992; Hardin, 1994; Sehgal et al., Waltham, Massachusetts 02254 1995; So and Rosbash, 1997). In addition, mutations § Department of Pathology in the two proteins (PER and TIM) alter or abolish the Brigham and Women's Hospital periodicity and phase of these rhythms, demonstrating Boston, Massachusetts 02115 that both proteins regulate their own transcription (Har- din et al., 1990; Sehgal et al., 1995; Marrus et al., 1996). Although there is no evidence indicating that the effects Summary on transcription are direct, PER contains a PAS domain, which has been shown to mediate interactions between We report the identification, characterization, and transcription factors (Huang et al., 1993; Lindebro et cloning of a novel Drosophila circadian rhythm gene, al., 1995). Most of these PAS-containing transcription dClock. The mutant, initially called Jrk, manifests dom- factors also contain the well-characterized basic helix- inant effects: heterozygous flies have a period alter- loop-helix (bHLH) DNA-binding domains (Crews, 1998). -
Genes Controlling Essential Cell-Cycle Functions in Drosophila Melanogaster
Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Genes controlling essential cell-cycle functions in Drosophila melanogaster Maurizio Gatti I and Bruce S. Baker 2 ~Dipartimento de Genetica e Biologia Molecolare, Universit/l di Roma 'La Sapienza', 00185 Roma, Italy; 2Department of Biological Sciences, Stanford University, Stanford, California 94305 USA On the basis of the hypothesis that mutants in genes controlling essential cell cycle functions in Drosophila should survive up to the larval-pupal transition, 59 such 'late lethals' were screened for those mutants affecting cell division. Examination of mitosis in brain neuroblasts revealed that 30 of these lethals cause disruptions in mitotic chromosome behavior. These mutants identify genes whose wild-type functions are important for: (1) progression through different steps of interphase, (2) the maintenance of mitotic chromosome integrity, (3) chromosome condensation, (4) spindle formation and/or function, and (5) completion of cytokinesis or completion of chromosome segregation. The presence of mitotic defects in late lethal mutants is correlated tightly with the presence of defective imaginal discs. Thus, the phenotypes of late lethality and poorly developed imaginal discs are together almost diagnostic of mutations in essential cell-cycle functions. The terminal phenotypes exhibited by these Drosophila mitotic mutants are remarkably similar to those observed in mammalian cell-cycle mutants, suggesting that these diverse organisms use a common genetic logic to regulate and integrate the events of the cell cycle. [Key Words: Cell-cycle mutants; Drosophila; mitosis] Received November 30, 1988; revised version accepted February 7, 1989. The exquisitely precise cyclic changes that eukaryotic review, see Simchen 1978; Ling 1981; Oakley 1981; chromosomes and cells undergo during mitotic and Wissmger and Wang 1983; Marcus et al. -
Important for Jet-Lagged Circadian Loops Mary Harrington
Commentaries Location, location, location: important for jet-lagged circadian loops Mary Harrington Department of Psychology, Smith College, Northampton, Massachusetts, USA. It is now believed that frequent jet lag or shifts of daily rhythms caused by feedback signal inhibiting the activational rotating shift work can lead to deleterious health outcomes. Indeed, many drive of CLK and ARNTL that led to their serious health problems, including breast cancer, stroke, and cardiovascu- own production. After some time, period/ lar disease, have been linked to an occupational history of shift work. This cryptochrome inhibition is released, and has heightened interest in better understanding the biological responses to CLK and ARNTL are free to begin the cycle jet lag and shift work, with the hope that this will pave the way to developing again. This is a simplified example of the compounds that can help people avoid their negative health consequences. molecular mechanism underlying circadian In this context, a report in this issue of the JCI takes us to a new level of rhythms; there are several other genes play- understanding of the molecular control of the resetting of the multitude of ing feedback roles as well. For example, the internal biological clocks disrupted in a mouse model of jet lag. genes encoding nuclear receptor subfamily 1, group D, member 1 (NR1D1; also known Jet lag can seem like a minor discomfort, kept aligned with the cycles of the planet in as REV-ERBa) and RAR-related orphan but studies are now suggesting that fre- part by the regulatory influence of a small receptor a (RORa) mediate a feedback loop quent jet lag or shifts of daily rhythms as group of neurons in a region of the hypo- to provide rhythmic inhibitory and activat- a result of rotating shift work can lead to thalamus known as the suprachiasmatic ing drive, respectively, to Arntl. -
Frequent Mutation of the E2F-4 Cell Cycle Gene in Primary Human Gastrointestinal Tumors'
ICANCER RESEARCH57. 2350-2353, June 5. 9971 Advances in Brief Frequent Mutation of the E2F-4 Cell Cycle Gene in Primary Human Gastrointestinal Tumors' Rhonda F. Soum, Jing Yin, Kara N. Smolinski, Tong-Tong Zou, Suna Wang, Ying-Qiang SM, Mun-Gan Rhyu, John Cottrell, John M. Abraham, Kelli Biden, Lisa Simms, Barbara Leggett, G. Steven Bova, Tom Frank, Steven M. Powell, Haruhiko Sugimura, Joanne Young, Noam Harpaz, Kenji Shimizu, Nagahide Matsubara, and Stephen J. Meltzer@ Departments of Medicine (GI Division) (R. F. S.. .1. Y., K. N. S., T-T. Z, S. W., Y-Q. S.. J. M. A., S. J. MI, Pathology fJ. C.. S. J. MI, and Greenebaum Cancer Center (J. M. A.. S. J. MI. University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center. Baltimore, Maryland 21201-1595; Department of Microbiology. Catholic Universirv Medical College. 137-701 Seoul, South Korea (M-G. RI; Glaxo Conjoint Gasiroenterology Laboratory, Royal Brisbane Hospital, Q4029 Herston, Australia fK. B., L S.. B. L, J. Y.J: Brady Urological Institute, Johns Hopkins University School of Medicine. Baltimore. Maryland 21287 (G. S. B.J; Department of Pathology, University of Michigan School of Medicine, Michigan 48109 IT. F.]: Department of Medicine/GI Division, University of Virginia, Charlottesville, Virginia 22908 (S. M. P.J; First Department of Pathology, Hamamatsu University School of Medicine, 431-31 Hamamatsu, Japan [H. S.]: Department of Pathology, Mt. Sinai University School of Medicine, New York. New York 10029 (N. H.]: and First Department ofSurgerv and Molecular Genetics, Okayama University Medical School, 700 Okayama. Japan (K. S. -
TIMELESS in Head and Neck Squamous Cell Carcinoma: a Systematic Review †
Extended Abstract TIMELESS in Head and Neck Squamous Cell Carcinoma: A Systematic Review † Piermichele Saracino 1,*, Claudia Arena 1, Marco Mascitti 2, Andrea Santarelli 2, Vera Panzarella 3 and Lucio Lo Russo 1 1 Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; [email protected] (C.A.); [email protected] (L.L.R.) 2 Department of Clinical Specialistic and Dental Sciences, Marche Polytechnic, 60131 Ancona, Italy; [email protected] (M.M.); [email protected] (A.S.) 3 Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; [email protected] * Correspondence: [email protected]; Tel.: +393332016671 † Presented at the XV National and III International Congress of the Italian Society of Oral Pathology and Medicine (SIPMO), Bari, Italy, 17–19 October 2019. Published: 11 December 2019 TIMELESS is one of the main circadian genes. Different roles are described, such as replication fork stability, cell survival after DNA damage or replication stress by promoting DNA repair. TIMELESS deficiency increases genomic instability and its reduction increases Rad51 and Rad52 foci formation during S phase [1]. TIMELESS and PARP1 operate in a complex to mediate DNA repair. It is also showed that alteration in circadian rhythm is associated with cancer development and tumor progression, such as chronic myeloid leukemia, hepatocellular carcinoma, and breast cancer [2]. We wanted to summarize the role of TIMELESS in head and neck squamous cell carcinoma. To do so, we performed a literature review using these keywords: TIMELESS [All Fields] AND (“neoplasms” [MeSH Terms] OR “neoplasms” [All Fields] OR “cancer” [All Fields]). -
Ribosome Profiling Reveals an Important Role for Translational Control in Circadian Gene Expression
Downloaded from genome.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Research Ribosome profiling reveals an important role for translational control in circadian gene expression Christopher Jang,1,4 Nicholas F. Lahens,2,4 John B. Hogenesch,2 and Amita Sehgal1,3 1Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA; 2Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA; 3Howard Hughes Medical Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA Physiological and behavioral circadian rhythms are driven by a conserved transcriptional/translational negative feedback loop in mammals. Although most core clock factors are transcription factors, post-transcriptional control introduces delays that are critical for circadian oscillations. Little work has been done on circadian regulation of translation, so to address this deficit we conducted ribosome profiling experiments in a human cell model for an autonomous clock. We found that most rhythmic gene expression occurs with little delay between transcription and translation, suggesting that the lag in the ac- cumulation of some clock proteins relative to their mRNAs does not arise from regulated translation. Nevertheless, we found that translation occurs in a circadian fashion for many genes, sometimes imposing an additional level of control on rhythmically expressed mRNAs and, in other cases, conferring rhythms on noncycling mRNAs. Most cyclically tran- scribed RNAs are translated at one of two major times in a 24-h day, while rhythmic translation of most noncyclic RNAs is phased to a single time of day. -
Circadian Rhythms from Flies to Human
insight review articles Circadian rhythms from flies to human Satchidananda Panda*†, John B. Hogenesch† & Steve A. Kay*† *Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA (e-mail: [email protected]) †Genomics Institute of Novartis Research Foundation, San Diego, California 92121, USA In this era of jet travel, our body ‘remembers’ the previous time zone, such that when we travel, our sleep–wake pattern, mental alertness, eating habits and many other physiological processes temporarily suffer the consequences of time displacement until we adjust to the new time zone. Although the existence of a circadian clock in humans had been postulated for decades, an understanding of the molecular mechanisms has required the full complement of research tools. To gain the initial insights into circadian mechanisms, researchers turned to genetically tractable model organisms such as Drosophila. he rotation of the presence of an internal Earth causes predict- pacemaker1. Once emerged, adult able changes in light flies restrict flight, foraging and and temperature in mating activities to the day (or our natural environ- subjective day), while they tend to Tment. Accordingly, natural selec- ‘sleep’ (that is, they are relatively tion has favoured the evolution unresponsive to sensory stimuli of circadian (from the Latin and exhibit rest homeostasis2,3) circa, meaning ‘about’, and dies, during the night. meaning ‘day’) clocks or Circadian regulation of such biological clocks — endogenous physiology and behaviour results cellular mechanisms for keeping track of time. These from coordination of the activities of multiple tissues and clocks impart a survival advantage by enabling an cell types. An example is the consolidation of feeding behav- organism to anticipate daily environmental changes and iour to the day phase, which involves regulation of the sensi- thus tailor its behaviour and physiology to the appropriate tivity of chemosensory organs to locate food, activity of the time of the day. -
PERIOD-Controlled Deadenylation of the Timeless Transcript in the Drosophila Circadian Clock
PERIOD-controlled deadenylation of the timeless transcript in the Drosophila circadian clock Brigitte Grimaa, Christian Papina, Béatrice Martina, Elisabeth Chélota, Prishila Ponienb, Eric Jacquetb, and François Rouyera,1 aInstitut des Neurosciences Paris-Saclay, Université Paris-Sud, Université Paris-Saclay, CNRS, 91190 Gif-sur-Yvette, France; and bInstitut de Chimie des Substances Naturelles, Université Paris-Saclay, CNRS, 91190 Gif-sur-Yvette, France Edited by Michael Rosbash, Howard Hughes Medical Institute/Brandeis University, Waltham, MA, and approved February 7, 2019 (received for review August 21, 2018) The Drosophila circadian oscillator relies on a negative transcriptional length affects numerous transcripts and contributes to the os- feedback loop, in which the PERIOD (PER) and TIMELESS (TIM) pro- cillations of the corresponding protein levels (23, 24). A key teins repress the expression of their own gene by inhibiting the ac- player in regulating poly(A) length is the CCR4–NOT complex tivity of the CLOCK (CLK) and CYCLE (CYC) transcription factors. A (25), which contains two deadenylase components encoded by series of posttranslational modifications contribute to the oscillations the Pop2 (homolog of Schizosaccharomyces pombe caf1) and twin of the PER and TIM proteins but few posttranscriptional mechanisms (homolog of S. pombe ccr4) genes in flies (26). In this study, we have been described that affect mRNA stability. Here we report that reveal an example of the regulation of mRNA oscillations of a down-regulation of the POP2 deadenylase, a key component of the core clock gene, timeless, through the control of the poly- CCR4–NOT deadenylation complex, alters behavioral rhythms. Down- adenylation of its mRNA by the POP2 deadenylase.