Cycling vrille Expression Is Required for a Functional Drosophila Clock

We identified a novel regulatory loop within Drosophila's circadian clock. A screen for clock-controlled genes recovered vrille (vri), a transcription factor essential for embryonic development. vri is expressed in circadian pacemaker cells in larval and adult brains. vri RNA levels oscillate with a circadian rhythm. Cycling is directly regulated by the transcription factors dCLOCK and CYCLE, which are also required for oscillations of period and timeless RNA. Eliminating the normal vri cycle suppresses period and timeless expression and causes long-period behavioral rhythms and arrhythmicity, indicating that cycling vri is required for a functional Drosophila clock. We also show that dCLOCK and VRI independently regulate levels of a neuropeptide, pigment dispersing factor, which appears to regulate overt behavior.

[1]  G. Eichele,et al.  The mPer2 gene encodes a functional component of the mammalian circadian clock , 1999, Nature.

[2]  Michael W Young,et al.  The Drosophila Clock Gene double-time Encodes a Protein Closely Related to Human Casein Kinase Iε , 1998, Cell.

[3]  D. P. King,et al.  Role of the CLOCK protein in the mammalian circadian mechanism. , 1998, Science.

[4]  S. Kay,et al.  Independent photoreceptive circadian clocks throughout Drosophila. , 1997, Science.

[5]  Xiaolan Zhang,et al.  A Molecular Rhythm Mediating Circadian Clock Output in Drosophila , 1998, Neuron.

[6]  M. W. Young,et al.  Changes in abundance or structure of the per gene product can alter periodicity of the Drosophila clock , 1987, Nature.

[7]  I. Edery,et al.  The Drosophila CLOCK Protein Undergoes Daily Rhythms in Abundance, Phosphorylation, and Interactions with the PER–TIM Complex , 1998, Neuron.

[8]  Thomas K. Darlington,et al.  Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. , 1998, Science.

[9]  C. Helfrich-Förster,et al.  Development of pigment‐dispersing hormone‐immunoreactive neurons in the nervous system of Drosophila melanogaster , 1997, The Journal of comparative neurology.

[10]  M. W. Young,et al.  double-time Is a Novel Drosophila Clock Gene that Regulates PERIOD Protein Accumulation , 1998, Cell.

[11]  L. Vosshall,et al.  Circadian rhythms in drosophila can be driven by period expression in a restricted group of central brain cells , 1995, Neuron.

[12]  M. W. Young.  The molecular control of circadian behavioral rhythms and their entrainment in Drosophila. , 1998, Annual review of biochemistry.

[13]  D. Sidote,et al.  Circadian Regulation of a Drosophila Homolog of the Mammalian Clock Gene: PER and TIM Function as Positive Regulators , 1998, Molecular and Cellular Biology.

[14]  J. C. Hall,et al.  Isolation and Chronobiological Analysis of a Neuropeptide Pigment-Dispersing Factor Gene in Drosophila melanogaster , 1998, Journal of biological rhythms.

[15]  Jeffrey C. Hall,et al.  A Mutant Drosophila Homolog of Mammalian Clock Disrupts Circadian Rhythms and Transcription of period and timeless , 1998, Cell.

[16]  F. Fleury-Olela,et al.  The rat hepatic leukemia factor (HLF) gene encodes two transcriptional activators with distinct circadian rhythms, tissue distributions and target preferences. , 1995, The EMBO journal.

[17]  Jeffrey C. Hall,et al.  CRY, a Drosophila Clock and Light-Regulated Cryptochrome, Is a Major Contributor to Circadian Rhythm Resetting and Photosensitivity , 1998, Cell.

[18]  Mark J. Zylka,et al.  A Molecular Mechanism Regulating Rhythmic Output from the Suprachiasmatic Circadian Clock , 1999, Cell.

[19]  U. Schibler,et al.  Expression of the liver-enriched transcriptional activator protein DBP follows a stringent circadian rhythm , 1990, Cell.

[20]  G. Wanner,et al.  The two PAR leucine zipper proteins, TEF and DBP, display similar circadian and tissue‐specific expression, but have different target promoter preferences. , 1996, The EMBO journal.

[21]  B. Petri,et al.  Pigment-Dispersing Hormone Shifts the Phase of the Circadian Pacemaker of the Cockroach Leucophaea maderae , 1997, The Journal of Neuroscience.

[22]  D. Allen,et al.  A circadian enhancer mediates PER-dependent mRNA cycling in Drosophila melanogaster , 1997, Molecular and cellular biology.

[23]  Ueli Schibler,et al.  The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behavior , 1997, The EMBO journal.

[24]  R J Konopka,et al.  Clock mutants of Drosophila melanogaster. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[25]  D. P. King,et al.  Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. , 1994, Science.

[26]  B. Amati,et al.  Distinct DNA binding preferences for the c-Myc/Max and Max/Max dimers. , 1993, Nucleic acids research.

[27]  D. V. Leenen,et al.  Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms , 1999, Nature.

[28]  F. Jackson,et al.  A new biological rhythm mutant of Drosophila melanogaster that identifies a gene with an essential embryonic function. , 1993, Genetics.

[29]  R. Terracol,et al.  The vrille gene of Drosophila is a maternal enhancer of decapentaplegic and encodes a new member of the bZIP family of transcription factors. , 1997, Genetics.

[30]  J. Giebultowicz,et al.  Circadian clock in Malpighian tubules , 1997, Nature.

[31]  J. C. Hall,et al.  Spatial and Temporal Expression of the period andtimeless Genes in the Developing Nervous System ofDrosophila: Newly Identified Pacemaker Candidates and Novel Features of Clock Gene Product Cycling , 1997, The Journal of Neuroscience.

[32]  Jeffrey C. Hall,et al.  The cryb Mutation Identifies Cryptochrome as a Circadian Photoreceptor in Drosophila , 1998, Cell.

[33]  Thomas K. Darlington,et al.  Light-dependent sequestration of TIMELESS by CRYPTOCHROME. , 1999, Science.

[34]  Jeffrey C. Hall,et al.  CYCLE Is a Second bHLH-PAS Clock Protein Essential for Circadian Rhythmicity and Transcription of Drosophila period and timeless , 1998, Cell.

[35]  C. Helfrich-Förster.  Robust circadian rhythmicity of Drosophila melanogaster requires the presence of lateral neurons: a brain-behavioral study of disconnected mutants , 1998, Journal of Comparative Physiology A.

[36]  H. Hurst,et al.  Transcriptional repression by a novel member of the bZIP family of transcription factors , 1992, Molecular and cellular biology.

[37]  D. S. Hsu,et al.  Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. , 1998, Science.

[38]  N. Perrimon,et al.  Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. , 1993, Development.

[39]  Jeffrey C. Hall,et al.  Novel Features of Drosophila period Transcription Revealed by Real-Time Luciferase Reporting , 1996, Neuron.

[40]  P. Hardin,et al.  Drosophila Photoreceptors Contain an Autonomous Circadian Oscillator That Can Function without period mRNA Cycling , 1998, The Journal of Neuroscience.

[41]  A. Sehgal,et al.  Ontogeny of a biological clock in Drosophila melanogaster. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Dunlap.  Molecular Bases for Circadian Clocks , 1999, Cell.

[43]  C. Helfrich-Förster.  The period clock gene is expressed in central nervous system neurons which also produce a neuropeptide that reveals the projections of circadian pacemaker cells within the brain of Drosophila melanogaster. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Richard A. Flavell,et al.  All's well that ends dead , 1999 .

[45]  Jeffrey C. Hall,et al.  A promoterless period gene mediates behavioral rhythmicity and cyclical per expression in a restricted subset of the drosophila nervous system , 1994, Neuron.