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Michael Rosbash - One of the best experts on this subject based on the ideXlab platform.
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The timSL Mutant of the Drosophila Rhythm Gene timeless Manifests Allele-Specific Interactions with Period Gene Mutants
Neuron, 1996Co-Authors: Joan E. Rutila, Jeffrey C Hall, Hongkui Zeng, Kathryn D Curtin, Michael RosbashAbstract:To identify new components of the Drosophila circadian clock, we screened chemically mutagenized flies for suppressors or enhancers of the long Periods characteristic of the Period (per) mutant allele perL. We isolated a novel mutant that maps to the rhythm Gene timeless (tim). This novel allele, timSL, alters the temporal pattern of perL protein nuclear localization and restores temperature compensation to perL flies. timSL more Generally manifests specific interactions with different per alleles. The identification of this first Period-altering tim allele provides further evidence that TIM is a major component of the clock, and the allele-specific interactions with PER provide evidence that the PER/TIM heterodimer is a unit of circadian function. Although timSL fails to restore PER-L/TIM temperature insensitivity in yeast, it alters the TIM phosphorylation pattern during the late night. The effects on phosphorylation suggest that timSL functions as a partial bypass suppressor of perL and provide evidence that the TIM phosphorylation program contributes to the circadian timekeeping mechanism.
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temporal phosphorylation of the drosophila Period protein
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Isaac Edery, Laurence J. Zwiebel, Marie E Dembinska, Michael RosbashAbstract:Abstract The Period Gene (per) is required for Drosophila melanogaster to manifest circadian (congruent to 24 hr) rhythms. We report here that per protein (PER) undergoes daily oscillations in apparent molecular mass as well as abundance. The mobility changes are largely or exclusively due to multiple phosphorylation events. The temporal profile of the classic short-Period form of PER (PERS) is altered in a manner consistent with the mutant strain's behavioral phenotype. As changes in abundance and phosphorylation persist under constant environmental conditions, they reflect or contribute to a free-running rhythm. We suggest that the phosphorylation status of PER is an important determinant in the Drosophila clock's time-keeping mechanism.
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a promoterless Period Gene mediates behavioral rhythmicity and cyclical per expression in a restricted subset of the drosophila nervous system
Neuron, 1994Co-Authors: B. Frisch, Paul E Hardin, Michael Rosbash, Melanie J Hamblencoyle, Jeffrey C HallAbstract:Transgenic flies carrying a 7.2 kb piece of DNA from the Period (per) Gene were analyzed for the presence of circadian locomotor activity rhythms and fluctuations of per-encoded mRNA and protein. The 5' end of this genomic fragment is within the first intron, which precedes the coding region. This promotorless fragment could rescue circadian behavioral rhythms and mediate spatial expression of PER in a subset of wild-type per cells within the CNS and PNS. In one behaviorally rhythmic line, PER protein was found in only "per lateral neurons." In the rhythmic transgenics, per mRNA and protein levels undergo circadian cycling, as previously described for wild type. Cycling of PER in brain cells of flies carrying the same 7.2 kb piece of per DNA under the control of a heat shock promoter corroborated the hypothesis that per's molecular cyclings and behavioral rhythmicity are causally related.
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phase shifting of the circadian clock by induction of the drosophila Period protein
Science, 1994Co-Authors: Isaac Edery, Joan E. Rutila, Michael RosbashAbstract:Virtually all organisms manifest circadian (24-hour) rhythms, governed by an ill-defined endogenous pacemaker or clock. Several lines of evidence suggest that the Drosophila melanogaster Period Gene product PER is a clock component. If PER were central to the time-keeping mechanism, a transient increase in its concentration would cause a stable shift in the phase of the clock. Therefore, transgenic flies bearing a heat-inducible copy of PER were subjected to temperature pulses. This treatment caused long-lasting phase shifts in the locomotor activity circadian rhythm, a result that supports the contention that PER is a bona fide clock component.
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A promoterless Period Gene mediates behavioral rhythmicity and cyclical per expression in a restricted subset of the Drosophila nervous system.
Neuron, 1994Co-Authors: B. Frisch, Paul E Hardin, Michael Rosbash, Melanie J. Hamblen-coyle, Jeffrey C HallAbstract:Summary Transgenic flies carrying a 7.2 kb piece of DNA from the Period (per) Gene were analyzed for the presence of circadian locomotor activity rhythms and fluctuations of per -encoded mRNA and protein. The 5′ end of this genomic fragment is within the first intron, which precedes the coding region. This promotorless fragment could rescue circadian behavioral rhythms and mediate spatial expression of PER in a subset of wild-type per cells within the CNS and PNS. In one behaviorally rhythmic line, PER protein was found in only " per lateral neurons." In the rhythmic transgenics, per mRNA and protein levels undergo circadian cycling, as previously described for wild type. Cycling of PER in brain cells of flies carrying the same 7.2 kb piece of per DNA under the control of a heat shock promotor corroborated the hypothesis that per 's molecular cyclings and behavioral rhythmicity are causally related.
Jeffrey C Hall - One of the best experts on this subject based on the ideXlab platform.
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Multiple circadian-regulated elements contribute to cycling Period Gene expression in Drosophila
The EMBO journal, 1997Co-Authors: Ralf Stanewsky, Jeffrey D. Plautz, Creston F. Jamison, Steve A. Kay, Jeffrey C HallAbstract:A new regulatory element necessary for the correct temporal expression of the Period (per) Gene was identified by monitoring real-time per expression in living individual flies carrying two different Period-luciferase transGenes. luciferase RNA driven from only the per promoter was not sufficient to replicate the normal pattern of per RNA cycling; however, a per-luc fusion RNA driven from a transGene containing additional per sequences cycled identically to endogenous per. The results indicate the existence of at least two circadian-regulated elements--one within the promoter and one within the transcribed portion of the per Gene. Phase and amplitude analysis of both per-luc transGenes revealed that normal per expression requires the regulation of these elements at distinct phases and suggests a mechanism by which biological clocks sustain high-amplitude feedback oscillations.
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Quantitative analysis of Drosophila Period Gene transcription in living animals.
Journal of biological rhythms, 1997Co-Authors: Jeffrey D. Plautz, Jeffrey C Hall, Creston F. Jamison, Martin Straume, Ralf Stanewsky, Christian Brandes, Harold B. Dowse, Steve A. KayAbstract:To determine the in vivo regulatory pattern of the clock Gene Period (per), the authors recently developed transgenic Drosophila carrying a luciferase cDNA fused to the promoter region of per. They have now carried out noninvasive, high time-resolution experiments allowing high-throughput monitoring of circadian bioluminescence rhythms in individual living adults for several days. This immediately solved several problems (resulting directly from individual asynchrony within a population) that have accompanied previous biochemical experiments in which groups of animals were sacrificed at each time point. Furthermore, the authors have developed numerical analysis methods for automatically determining rhythmicity associated with bioluminescence records from single flies. This has revealed some features of per Gene transcription that were previously unappreciated and provides a General strategy for the analysis of rhythmic time series in the study of molecular rhythms.
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The timSL Mutant of the Drosophila Rhythm Gene timeless Manifests Allele-Specific Interactions with Period Gene Mutants
Neuron, 1996Co-Authors: Joan E. Rutila, Jeffrey C Hall, Hongkui Zeng, Kathryn D Curtin, Michael RosbashAbstract:To identify new components of the Drosophila circadian clock, we screened chemically mutagenized flies for suppressors or enhancers of the long Periods characteristic of the Period (per) mutant allele perL. We isolated a novel mutant that maps to the rhythm Gene timeless (tim). This novel allele, timSL, alters the temporal pattern of perL protein nuclear localization and restores temperature compensation to perL flies. timSL more Generally manifests specific interactions with different per alleles. The identification of this first Period-altering tim allele provides further evidence that TIM is a major component of the clock, and the allele-specific interactions with PER provide evidence that the PER/TIM heterodimer is a unit of circadian function. Although timSL fails to restore PER-L/TIM temperature insensitivity in yeast, it alters the TIM phosphorylation pattern during the late night. The effects on phosphorylation suggest that timSL functions as a partial bypass suppressor of perL and provide evidence that the TIM phosphorylation program contributes to the circadian timekeeping mechanism.
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a promoterless Period Gene mediates behavioral rhythmicity and cyclical per expression in a restricted subset of the drosophila nervous system
Neuron, 1994Co-Authors: B. Frisch, Paul E Hardin, Michael Rosbash, Melanie J Hamblencoyle, Jeffrey C HallAbstract:Transgenic flies carrying a 7.2 kb piece of DNA from the Period (per) Gene were analyzed for the presence of circadian locomotor activity rhythms and fluctuations of per-encoded mRNA and protein. The 5' end of this genomic fragment is within the first intron, which precedes the coding region. This promotorless fragment could rescue circadian behavioral rhythms and mediate spatial expression of PER in a subset of wild-type per cells within the CNS and PNS. In one behaviorally rhythmic line, PER protein was found in only "per lateral neurons." In the rhythmic transgenics, per mRNA and protein levels undergo circadian cycling, as previously described for wild type. Cycling of PER in brain cells of flies carrying the same 7.2 kb piece of per DNA under the control of a heat shock promoter corroborated the hypothesis that per's molecular cyclings and behavioral rhythmicity are causally related.
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A promoterless Period Gene mediates behavioral rhythmicity and cyclical per expression in a restricted subset of the Drosophila nervous system.
Neuron, 1994Co-Authors: B. Frisch, Paul E Hardin, Michael Rosbash, Melanie J. Hamblen-coyle, Jeffrey C HallAbstract:Summary Transgenic flies carrying a 7.2 kb piece of DNA from the Period (per) Gene were analyzed for the presence of circadian locomotor activity rhythms and fluctuations of per -encoded mRNA and protein. The 5′ end of this genomic fragment is within the first intron, which precedes the coding region. This promotorless fragment could rescue circadian behavioral rhythms and mediate spatial expression of PER in a subset of wild-type per cells within the CNS and PNS. In one behaviorally rhythmic line, PER protein was found in only " per lateral neurons." In the rhythmic transgenics, per mRNA and protein levels undergo circadian cycling, as previously described for wild type. Cycling of PER in brain cells of flies carrying the same 7.2 kb piece of per DNA under the control of a heat shock promotor corroborated the hypothesis that per 's molecular cyclings and behavioral rhythmicity are causally related.
Steven M. Reppert - One of the best experts on this subject based on the ideXlab platform.
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three Period homologs in mammals differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain
Neuron, 1998Co-Authors: Mark J. Zylka, David R. Weaver, Lauren P Shearman, Steven M. ReppertAbstract:Abstract We have cloned and characterized the mouse cDNA of a third mammalian homolog of the Drosophila Period Gene and designated it mPer3 . The mPER3 protein shows ∼37% amino acid identity with mPER1 and mPER2 proteins. The three mammalian PER proteins share several regions of sequence homology, and each contains a protein dimerization PAS domain. mPer3 RNA levels oscillate in the suprachiasmatic nuclei (SCN) and eyes. In the SCN, mPer3 RNA levels are not acutely altered by light exposure at different times during subjective night. This contrasts with the acute induction by light of mPer1 and mPer2 RNA levels during early and late subjective night. mPer3 is widely expressed in tissues outside of brain. In liver, skeletal muscle, and testis, mPer RNAs exhibit prominent, synchronous circadian oscillations. The results highlight the differential light responses among the three mammalian Per Genes in the SCN and raise the possibility of circadian oscillators in mammals outside of brain and retina.
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three Period homologs in mammals differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain
Neuron, 1998Co-Authors: Mark J. Zylka, David R. Weaver, Lauren P Shearman, Steven M. ReppertAbstract:We have cloned and characterized the mouse cDNA of a third mammalian homolog of the Drosophila Period Gene and designated it mPer3. The mPER3 protein shows approximately 37% amino acid identity with mPER1 and mPER2 proteins. The three mammalian PER proteins share several regions of sequence homology, and each contains a protein dimerization PAS domain. mPer3 RNA levels oscillate in the suprachiasmatic nuclei (SCN) and eyes. In the SCN, mPer3 RNA levels are not acutely altered by light exposure at different times during subjective night. This contrasts with the acute induction by light of mPer1 and mPer2 RNA levels during early and late subjective night. mPer3 is widely expressed in tissues outside of brain. In liver, skeletal muscle, and testis, mPer RNAs exhibit prominent, synchronous circadian oscillations. The results highlight the differential light responses among the three mammalian Per Genes in the SCN and raise the possibility of circadian oscillators in mammals outside of brain and retina.
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Two Period Homologs: Circadian Expression and Photic Regulation in the Suprachiasmatic Nuclei
Neuron, 1997Co-Authors: Lauren P Shearman, David R. Weaver, Mark J. Zylka, Lee F. Kolakowski, Steven M. ReppertAbstract:We have characterized a mammalian homolog of the Drosophila Period Gene and designated it Per2. The PER2 protein shows >40% amino acid identity to the protein of another mammalian per homolog (designated Per1) that was recently cloned and characterized. Both PER1 and PER2 proteins share several regions of homology with the Drosophila PER protein, including the protein dimerization PAS domain. PhyloGenetic analysis supports the existence of a family of mammalian per Genes. In the mouse, Per1 and Per2 RNA levels exhibit circadian rhythms in the SCN and eyes, sites of circadian clocks. Both Per1 and Per2 RNAs in the SCN are increased by light exposure during subjective night but not during subjective day. The results advance our knowledge of candidate clock elements in mammals.
Paul E Hardin - One of the best experts on this subject based on the ideXlab platform.
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a promoterless Period Gene mediates behavioral rhythmicity and cyclical per expression in a restricted subset of the drosophila nervous system
Neuron, 1994Co-Authors: B. Frisch, Paul E Hardin, Michael Rosbash, Melanie J Hamblencoyle, Jeffrey C HallAbstract:Transgenic flies carrying a 7.2 kb piece of DNA from the Period (per) Gene were analyzed for the presence of circadian locomotor activity rhythms and fluctuations of per-encoded mRNA and protein. The 5' end of this genomic fragment is within the first intron, which precedes the coding region. This promotorless fragment could rescue circadian behavioral rhythms and mediate spatial expression of PER in a subset of wild-type per cells within the CNS and PNS. In one behaviorally rhythmic line, PER protein was found in only "per lateral neurons." In the rhythmic transgenics, per mRNA and protein levels undergo circadian cycling, as previously described for wild type. Cycling of PER in brain cells of flies carrying the same 7.2 kb piece of per DNA under the control of a heat shock promoter corroborated the hypothesis that per's molecular cyclings and behavioral rhythmicity are causally related.
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A promoterless Period Gene mediates behavioral rhythmicity and cyclical per expression in a restricted subset of the Drosophila nervous system.
Neuron, 1994Co-Authors: B. Frisch, Paul E Hardin, Michael Rosbash, Melanie J. Hamblen-coyle, Jeffrey C HallAbstract:Summary Transgenic flies carrying a 7.2 kb piece of DNA from the Period (per) Gene were analyzed for the presence of circadian locomotor activity rhythms and fluctuations of per -encoded mRNA and protein. The 5′ end of this genomic fragment is within the first intron, which precedes the coding region. This promotorless fragment could rescue circadian behavioral rhythms and mediate spatial expression of PER in a subset of wild-type per cells within the CNS and PNS. In one behaviorally rhythmic line, PER protein was found in only " per lateral neurons." In the rhythmic transgenics, per mRNA and protein levels undergo circadian cycling, as previously described for wild type. Cycling of PER in brain cells of flies carrying the same 7.2 kb piece of per DNA under the control of a heat shock promotor corroborated the hypothesis that per 's molecular cyclings and behavioral rhythmicity are causally related.
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Circadian oscillations in Period Gene mRNA levels are transcriptionally regulated.
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Paul E Hardin, Jeffrey C Hall, Michael RosbashAbstract:Abstract The Period (per) Gene is involved in regulating circadian rhythms in Drosophila melanogaster. The per Gene is expressed in a circadian manner, where fluctuations in per mRNA abundance are influenced by its own translation product, which also cycles in abundance. Since per Gene expression is necessary for circadian rhythmicity, we sought to determine how certain features of this feedback loop operate. The results of this study reveal that fluctuations in per mRNA are primarily controlled by fluctuations in per Gene transcription, that per mRNA has a relatively short half-life, and that sequences sufficient to drive per mRNA cycling are present in 1.3 kilobases of 5' flanking sequences. These and other results indicate that the per feedback loop has all of the basic properties necessary to be a component of a circadian oscillator.
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a post transcriptional mechanism contributes to circadian cycling of a per beta galactosidase fusion protein
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Laurence J. Zwiebel, Paul E Hardin, Jeffrey C Hall, Michael RosbashAbstract:Abstract The Period Gene (per) of Drosophila melanogaster affects circadian rhythms. Circadian fluctuations in per mRNA levels are thought to contribute to circadian fluctuations in per protein levels in the heads of adult flies. To address the mechanisms underlying these oscillatory phenomena, we have analyzed RNA and protein cycling from two per-beta-galactosidase fusion Genes. These studies demonstrate that 5' noncoding sequences from per are sufficient to cause the fusion mRNA levels to cycle in a wild-type (rhythmic) background. Protein cycling requires additional sequences derived from the per coding region. The data suggest that there is a per-dependent posttranscriptional mechanism that is under circadian clock control required for per protein levels to fluctuate in a rhythmic fashion.
David R. Weaver - One of the best experts on this subject based on the ideXlab platform.
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distinct patterns of Period Gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: William J Schwartz, Mahboubeh Tavakolinezhad, Christopher M Lambert, David R. Weaver, Horacio O De La IglesiaAbstract:The circadian clock in the mammalian hypothalamic suprachiasmatic nucleus (SCN) is entrained by the ambient light/dark cycle, which differentially acts to cause the clock to advance or delay. Light-induced changes in the rhythmic expression of SCN clock Genes are believed to be a critical step in this process, but how the two entrainment modalities—advances vs. delays—engage the molecular clockwork remains incompletely understood. We investigated molecular substrates of photic entrainment of the clock in the SCN by stably entraining hamsters to T cycles (non–24-h light/dark cycles) consisting of a single 1-h light pulse repeated as either a short (23.33-h) or a long (24.67-h) cycle; under these conditions, the light pulse of the short cycle acts as “dawn,” whereas that of the long cycle acts as “dusk.” Analyses of the expression of the photoinducible and rhythmic clock Genes Period 1 and 2 (Per1 and Per2) in the SCN revealed fundamental differences under these two entrainment modes. Light at dawn advanced the clock, advancing the onset of the Per1 mRNA rhythm and acutely increasing mRNA transcription, whereas light at dusk delayed the clock, delaying the offset of the Per2 mRNA rhythm and tonically increasing mRNA stability. The results suggest that the underlying molecular mechanisms of circadian entrainment differ with morning (advancing) or evening (delaying) light exposure, and such differences may reflect how entrainment takes place in nocturnal animals under natural conditions.
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Photic induction of Period Gene expression is reduced in Clock mutant mice
Neuroreport, 1999Co-Authors: Lauren P Shearman, David R. WeaverAbstract:The Clock mutation leads to abnormal circadian behavior and defective transcriptional activity of CLOCK, a basic helix-loop-helix (bHLH)/PAS protein. In situ hybridization was used to assess whether the Clock mutation affects the photic induction of mPer1, mPer2, and c-fos in the mouse suprachiasmatic nucleus (SCN). Exposure of wild-type mice to a 15 min light pulse at night rapidly induced expression of c-fos mRNA, with mPer1 and mPer2 mRNAs peaking later. Light exposure also increased c-fos, mPer1 and mPer2 mRNA levels in the SCN of homozygous Clock mutant mice, but the amplitude of the response to light was significantly reduced. Clock appears to play a role in circadian photoreception that is distinct from its role in the circadian oscillatory mechanism.
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three Period homologs in mammals differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain
Neuron, 1998Co-Authors: Mark J. Zylka, David R. Weaver, Lauren P Shearman, Steven M. ReppertAbstract:We have cloned and characterized the mouse cDNA of a third mammalian homolog of the Drosophila Period Gene and designated it mPer3. The mPER3 protein shows approximately 37% amino acid identity with mPER1 and mPER2 proteins. The three mammalian PER proteins share several regions of sequence homology, and each contains a protein dimerization PAS domain. mPer3 RNA levels oscillate in the suprachiasmatic nuclei (SCN) and eyes. In the SCN, mPer3 RNA levels are not acutely altered by light exposure at different times during subjective night. This contrasts with the acute induction by light of mPer1 and mPer2 RNA levels during early and late subjective night. mPer3 is widely expressed in tissues outside of brain. In liver, skeletal muscle, and testis, mPer RNAs exhibit prominent, synchronous circadian oscillations. The results highlight the differential light responses among the three mammalian Per Genes in the SCN and raise the possibility of circadian oscillators in mammals outside of brain and retina.
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three Period homologs in mammals differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain
Neuron, 1998Co-Authors: Mark J. Zylka, David R. Weaver, Lauren P Shearman, Steven M. ReppertAbstract:Abstract We have cloned and characterized the mouse cDNA of a third mammalian homolog of the Drosophila Period Gene and designated it mPer3 . The mPER3 protein shows ∼37% amino acid identity with mPER1 and mPER2 proteins. The three mammalian PER proteins share several regions of sequence homology, and each contains a protein dimerization PAS domain. mPer3 RNA levels oscillate in the suprachiasmatic nuclei (SCN) and eyes. In the SCN, mPer3 RNA levels are not acutely altered by light exposure at different times during subjective night. This contrasts with the acute induction by light of mPer1 and mPer2 RNA levels during early and late subjective night. mPer3 is widely expressed in tissues outside of brain. In liver, skeletal muscle, and testis, mPer RNAs exhibit prominent, synchronous circadian oscillations. The results highlight the differential light responses among the three mammalian Per Genes in the SCN and raise the possibility of circadian oscillators in mammals outside of brain and retina.
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Two Period Homologs: Circadian Expression and Photic Regulation in the Suprachiasmatic Nuclei
Neuron, 1997Co-Authors: Lauren P Shearman, David R. Weaver, Mark J. Zylka, Lee F. Kolakowski, Steven M. ReppertAbstract:We have characterized a mammalian homolog of the Drosophila Period Gene and designated it Per2. The PER2 protein shows >40% amino acid identity to the protein of another mammalian per homolog (designated Per1) that was recently cloned and characterized. Both PER1 and PER2 proteins share several regions of homology with the Drosophila PER protein, including the protein dimerization PAS domain. PhyloGenetic analysis supports the existence of a family of mammalian per Genes. In the mouse, Per1 and Per2 RNA levels exhibit circadian rhythms in the SCN and eyes, sites of circadian clocks. Both Per1 and Per2 RNAs in the SCN are increased by light exposure during subjective night but not during subjective day. The results advance our knowledge of candidate clock elements in mammals.