RESUMO
The circadian clock mechanism in animals involves a transcriptional feedback loop in which the bHLH-PAS proteins CLOCK and BMAL1 form a transcriptional activator complex to activate the transcription of the Period and Cryptochrome genes, which in turn feed back to repress their own transcription. In the mouse liver, CLOCK and BMAL1 interact with the regulatory regions of thousands of genes, which are both cyclically and constitutively expressed. The circadian transcription in the liver is clustered in phase and this is accompanied by circadian occupancy of RNA polymerase II recruitment and initiation. These changes also lead to circadian fluctuations in histone H3 lysine4 trimethylation (H3K4me3) as well as H3 lysine9 acetylation (H3K9ac) and H3 lysine27 acetylation (H3K27ac). Thus, the circadian clock regulates global transcriptional poise and chromatin state by regulation of RNA polymerase II.
Assuntos
Fatores de Transcrição ARNTL/genética , Proteínas CLOCK/genética , Relógios Circadianos/genética , Mamíferos/genética , Fatores de Transcrição ARNTL/fisiologia , Acetilação , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas CLOCK/fisiologia , Expressão Gênica , Histonas/metabolismo , Humanos , Fígado/fisiologia , Lisina/metabolismo , Camundongos , Modelos Biológicos , RNA Polimerase II/metabolismo , Transcrição GênicaRESUMO
Forskolin, a highly specific activator of adenylate cyclase, produced both delay and advance phase shifts of the circadian rhythm recorded from the isolated eye of the marine mollusk Aplysia. The phase dependence of the response to forskolin was identical to that with serotonin, which also stimulates adenylate cyclase in the eye. The ability of agents to activate adenylate cyclase in homogenates was correlated with their ability to shift the phase of the circadian oscillator. These results along with earlier findings show that adenosine 3',5'-monophosphate mediates the effect of serotonin on the rhythm and regulates the phase of the circadian pacemaker in the eye of Aplysia.
Assuntos
Adenilil Ciclases/fisiologia , Ritmo Circadiano , Monofosfato de Adenosina/fisiologia , Animais , Aplysia/fisiologia , Ritmo Circadiano/efeitos dos fármacos , Colforsina , AMP Cíclico/fisiologia , Diterpenos/farmacologia , Olho/efeitos dos fármacos , Fenômenos Fisiológicos Oculares , Serotonina/farmacologiaRESUMO
Daily rhythms in many behavioral, physiological, and biochemical functions are generated by endogenous oscillators that function as internal 24-hour clocks. Under natural conditions, these oscillators are synchronized to the daily environmental cycle of light and darkness. Recent advances in locating circadian pacemakers in the brain and in establishing model systems promise to shed light on the cellular and biochemical mechanisms involved in the generation and regulation of circadian rhythms.
Assuntos
Ritmo Circadiano , Animais , AMP Cíclico/fisiologia , Humanos , Luz , Glândula Pineal/fisiologia , Núcleo Supraóptico/fisiologiaRESUMO
Modern molecular genetic and genomic approaches are revolutionizing the study of behavior in the mouse. "Reverse genetics" (from gene to phenotype) with targeted gene transfer provides a powerful tool to dissect behavior and has been used successfully to study the effects of null mutations in genes implicated in the regulation of long-term potentiation and spatial learning in mice. In addition, "forward genetics" (from phenotype to gene) with high-efficiency mutagenesis in the mouse can uncover unknown genes and has been used to isolate a behavioral mutant of the circadian system. With the recent availability of high-density genetic maps and physical mapping resources, positional cloning of virtually any mutation is now feasible in the mouse. Together, these approaches permit a molecular analysis of both known and previously unknown genes regulating behavior.
Assuntos
Comportamento Animal , Técnicas Genéticas , Genética Comportamental/métodos , Animais , Ritmo Circadiano/genética , Feminino , Aprendizagem , Potenciação de Longa Duração , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , MutagêneseRESUMO
The suprachiasmatic nuclei (SCN) of the hypothalamus comprise the primary pacemaker responsible for generation of circadian rhythms in mammals. Light stimuli that synchronize this circadian clock induce expression of the c-fos gene in rodent SCN, which suggests a possible role for Fos in circadian entrainment. Appropriate light stimuli also induce the expression of jun-B messenger RNA in the SCN of golden hamsters but only slightly elevate c-jun messenger RNA levels. In addition, light increases the amount of a protein complex in the SCN that binds specifically to sites on DNA known to mediate regulation by the AP-1 transcription factor. The photic regulation of both jun-B messenger RNA expression and AP-1 binding activity is dependent on circadian phase: only light stimuli that shift behavioral rhythms induce jun-B and AP-1 expression. Thus, light and the circadian pacemaker interact to regulate a specific set of immediate-early genes in the SCN that may participate in entrainment of the circadian clock.
Assuntos
Regulação da Expressão Gênica , Genes jun/fisiologia , Luz , Periodicidade , Proteínas Proto-Oncogênicas c-jun/biossíntese , RNA Mensageiro/biossíntese , Animais , Sequência de Bases , Cricetinae , Genes fos/fisiologia , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , Sondas RNA , Núcleo Supraquiasmático/fisiologia , Fatores de Tempo , Transcrição GênicaRESUMO
Mammalian circadian rhythms are regulated by a pacemaker within the suprachiasmatic nuclei (SCN) of the hypothalamus. The molecular mechanisms controlling the synchronization of the circadian pacemaker are unknown; however, immediate early gene (IEG) expression in the SCN is tightly correlated with entrainment of SCN-regulated rhythms. Antibodies were isolated that recognize the activated, phosphorylated form of the transcription factor cyclic adenosine monophosphate response element binding protein (CREB). Within minutes after exposure of hamsters to light, CREB in the SCN became phosphorylated on the transcriptional regulatory site, Ser133. CREB phosphorylation was dependent on circadian time: CREB became phosphorylated only at times during the circadian cycle when light induced IEG expression and caused phase shifts of circadian rhythms. These results implicate CREB in neuronal signaling in the hypothalamus and suggest that circadian clock gating of light-regulated molecular responses in the SCN occurs upstream of phosphorylation of CREB.
Assuntos
Ritmo Circadiano , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Luz , Núcleo Supraquiasmático/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Colforsina/farmacologia , Cricetinae , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/imunologia , Escuridão , Regulação da Expressão Gênica , Genes fos , Glutamatos/farmacologia , Ácido Glutâmico , Dados de Sequência Molecular , Células PC12 , Fosforilação , Cloreto de Potássio/farmacologia , Núcleo Supraquiasmático/efeitos dos fármacosRESUMO
Pineal opsin (P-opsin), an opsin from chick that is highly expressed in pineal but is not detectable in retina, was cloned by the polymerase chain reaction. It is likely that the P-opsin lineage diverged from the retinal opsins early in opsin evolution. The amino acid sequence of P-opsin is 42 to 46 percent identical to that of the retinal opsins. P-opsin is a seven-membrane spanning, G protein-linked receptor with a Schiff-base lysine in the seventh membrane span and a Schiff-base counterion in the third membrane span. The primary sequence of P-opsin suggests that it will be maximally sensitive to approximately 500-nanometer light and produce a slow and prolonged phototransduction response consistent with the nonvisual function of pineal photoreception.
Assuntos
Proteínas do Tecido Nervoso/química , Glândula Pineal/química , Opsinas de Bastonetes/química , Sequência de Aminoácidos , Animais , Proteínas Aviárias , Sequência de Bases , Evolução Biológica , Química Encefálica , Galinhas , Clonagem Molecular , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Estrutura Secundária de Proteína , RNA Mensageiro/análise , Retina/química , Opsinas de Bastonetes/análise , Opsinas de Bastonetes/genética , Opsinas de Bastonetes/fisiologia , Homologia de Sequência de AminoácidosRESUMO
In a search for genes that regulate circadian rhythms in mammals, the progeny of mice treated with N-ethyl-N-nitrosourea (ENU) were screened for circadian clock mutations. A semidominant mutation, Clock, that lengthens circadian period and abolishes persistence of rhythmicity was identified. Clock segregated as a single gene that mapped to the midportion of mouse chromosome 5, a region syntenic to human chromosome 4. The power of ENU mutagenesis combined with the ability to clone murine genes by map position provides a generally applicable approach to study complex behavior in mammals.
Assuntos
Mapeamento Cromossômico , Ritmo Circadiano/genética , Genes , Mutagênese , Animais , Cromossomos Humanos Par 4 , Etilnitrosoureia , Feminino , Genótipo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , FenótipoRESUMO
The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon (CKIepsilon), a homolog of the Drosophila circadian gene double-time. In vitro expression and functional studies of wild-type and tau mutant CKIepsilon enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKIepsilon can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIepsilon and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.
Assuntos
Ritmo Circadiano , Mutação Puntual , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Caseína Quinases , Proteínas de Ciclo Celular , Mapeamento Cromossômico , Ritmo Circadiano/genética , Clonagem Molecular , Cricetinae , Feminino , Heterozigoto , Humanos , Masculino , Mesocricetus , Camundongos , Repetições de Microssatélites , Dados de Sequência Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Circadianas Period , Fenótipo , Fosforilação , Reação em Cadeia da Polimerase , Polimorfismo Genético , Proteínas Quinases/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Núcleo Supraquiasmático/metabolismoRESUMO
The mouse Clock gene encodes a bHLH-PAS protein that regulates circadian rhythms and is related to transcription factors that act as heterodimers. Potential partners of CLOCK were isolated in a two-hybrid screen, and one, BMAL1, was coexpressed with CLOCK and PER1 at known circadian clock sites in brain and retina. CLOCK-BMAL1 heterodimers activated transcription from E-box elements, a type of transcription factor-binding site, found adjacent to the mouse per1 gene and from an identical E-box known to be important for per gene expression in Drosophila. Mutant CLOCK from the dominant-negative Clock allele and BMAL1 formed heterodimers that bound DNA but failed to activate transcription. Thus, CLOCK-BMAL1 heterodimers appear to drive the positive component of per transcriptional oscillations, which are thought to underlie circadian rhythmicity.
Assuntos
Ritmo Circadiano/fisiologia , Proteínas Nucleares/genética , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Ativação Transcricional , Fatores de Transcrição ARNTL , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Relógios Biológicos , Proteínas CLOCK , Proteínas de Ciclo Celular , Ritmo Circadiano/genética , Clonagem Molecular , Cricetinae , DNA/metabolismo , Dimerização , Retroalimentação , Expressão Gênica , Sequências Hélice-Alça-Hélice , Masculino , Mesocricetus , Camundongos , Mutação , Proteínas Nucleares/metabolismo , Proteínas Circadianas Period , Regiões Promotoras Genéticas , Retina/metabolismo , Núcleo Supraquiasmático/metabolismo , Transativadores/genética , Fatores de Transcrição/genéticaRESUMO
The circadian oscillator generates a rhythmic output with a period of about 24 hours. Despite extensive studies in several model systems, the biochemical mode of action has not yet been demonstrated for any of its components. Here, the Drosophila CLOCK protein was shown to induce transcription of the circadian rhythm genes period and timeless. dCLOCK functioned as a heterodimer with a Drosophila homolog of BMAL1. These proteins acted through an E-box sequence in the period promoter. The timeless promoter contains an 18-base pair element encompassing an E-box, which was sufficient to confer dCLOCK responsiveness to a reporter gene. PERIOD and TIMELESS proteins blocked dCLOCK's ability to transactivate their promoters via the E-box. Thus, dCLOCK drives expression of period and timeless, which in turn inhibit dCLOCK's activity and close the circadian loop.
Assuntos
Ritmo Circadiano/fisiologia , Proteínas de Drosophila , Proteínas de Insetos/genética , Proteínas Nucleares/genética , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Ativação Transcricional , Fatores de Transcrição ARNTL , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Relógios Biológicos , Proteínas CLOCK , Linhagem Celular , Núcleo Celular/metabolismo , Ritmo Circadiano/genética , Dimerização , Drosophila , Retroalimentação , Expressão Gênica , Sequências Hélice-Alça-Hélice , Proteínas de Insetos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Circadianas Period , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transativadores/genética , Fatores de Transcrição/genética , TransfecçãoRESUMO
Cryptochromes are photoactive pigments in the eye that have been proposed to function as circadian photopigments. Mice lacking the cryptochrome 2 blue-light photoreceptor gene (mCry2) were tested for circadian clock-related functions. The mutant mice had a lower sensitivity to acute light induction of mPer1 in the suprachiasmatic nucleus (SCN) but exhibited normal circadian oscillations of mPer1 and mCry1 messenger RNA in the SCN. Behaviorally, the mutants had an intrinsic circadian period about 1 hour longer than normal and exhibited high-amplitude phase shifts in response to light pulses administered at circadian time 17. These data are consistent with the hypothesis that CRY2 protein modulates circadian responses in mice and suggest that cryptochromes have a role in circadian photoreception in mammals.
Assuntos
Ritmo Circadiano/fisiologia , Proteínas de Drosophila , Proteínas do Olho , Flavoproteínas/fisiologia , Luz , Células Fotorreceptoras de Invertebrados , Células Fotorreceptoras de Vertebrados/fisiologia , Animais , Proteínas de Ciclo Celular , Criptocromos , Feminino , Flavoproteínas/genética , Regulação da Expressão Gênica , Marcação de Genes , Hibridização In Situ , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Mutação , Proteínas Nucleares/genética , Proteínas Circadianas Period , Receptores Acoplados a Proteínas G , Núcleo Supraquiasmático/metabolismoRESUMO
Chick pineal cells contain circadian oscillators that regulate a rhythm of melatonin biosynthesis. We explored the role of cAMP in regulating this melatonin rhythm. Chick pineal cells expressed a 24 hr oscillation of cAMP efflux with a waveform similar to that of melatonin. Elevation of cAMP in chick pineal cells stimulated melatonin. These results suggest that an oscillation of cAMP regulates the rhythm of melatonin. We investigated whether cAMP was a component of the circadian oscillator by determining the effects of 8-Br cAMP pulses on the phase of the circadian melatonin rhythm. Six hour pulses of 8-Br cAMP did not cause steady-state phase shifts of the rhythm. The acute regulation of melatonin by cAMP, the 24 hr oscillation of cAMP, and the inability of cAMP to phase-shift the melatonin rhythm strongly suggest that cAMP acts as an output signal of the circadian oscillator.
Assuntos
Ritmo Circadiano , AMP Cíclico/metabolismo , Melatonina/biossíntese , Glândula Pineal/metabolismo , 1-Metil-3-Isobutilxantina/farmacologia , Animais , Animais Recém-Nascidos , Galinhas , Colforsina/farmacologia , AMP Cíclico/análogos & derivados , Relação Dose-Resposta a Droga , Masculino , Glândula Pineal/citologiaRESUMO
Photic information entrains a circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the mammalian hypothalamus to environmental light/dark cycles. To determine whether light regulates c-fos gene expression in the SCN, we have measured c-fos mRNA levels in the SCN of the golden hamster. We report that, during the subjective night, light causes a rapid increase in levels of c-fos mRNA in the SCN. Light pulses of 5 min duration are sufficient to induce c-fos mRNA, and the highest mRNA levels occur 30 min following the onset of light. The minimum level of illumination required to induce an increase in c-fos mRNA is indistinguishable from the minimum irradiance that produces a phase shift in the hamster's circadian rhythm of activity. In addition, the induction of c-fos mRNA in the SCN by light is itself under circadian regulation. Light induction of c-fos mRNA occurs only during the subjective night, at circadian times when photic phase shifting of activity occurs. Taken together, these data suggest that c-fos may be a molecular component of the photic pathway for entrainment of mammalian circadian rhythms.
Assuntos
Ritmo Circadiano , Regulação da Expressão Gênica , Proteínas Proto-Oncogênicas/genética , Proto-Oncogenes , Núcleo Supraquiasmático/metabolismo , Animais , Cricetinae , Luz , Masculino , Mesocricetus , Hibridização de Ácido Nucleico , Proteínas Proto-Oncogênicas c-fos , RNA Mensageiro/biossíntese , Fatores de TempoRESUMO
A circadian clock regulates a number of diverse physiological functions in the vertebrate eye. In this study, we show that mRNA for the red-sensitive cone pigment, iodopsin, fluctuates with a circadian rhythm in chicken retina. Transcript levels increase in the late afternoon just prior to the time of cone disc shedding. Furthermore, iodopsin mRNA levels are regulated similarly by a circadian oscillator in primary cultures of dispersed embryonic chick retina. Nuclear run-on experiments show that the circadian regulation of iodopsin transcript abundance occurs at the level of gene transcription. Our results provide a demonstration of clock-regulated gene expression in a vertebrate preparation maintained in cell culture.
Assuntos
Ritmo Circadiano , Expressão Gênica , Células Fotorreceptoras/fisiologia , Retina/embriologia , Pigmentos da Retina/genética , Opsinas de Bastonetes , Animais , Células Cultivadas , Embrião de Galinha , Células Fotorreceptoras/embriologia , RNA Mensageiro/metabolismo , Retina/citologia , Transcrição GênicaRESUMO
We report the cloning and mapping of mouse (mTim) and human (hTIM) orthologs of the Drosophila timeless (dtim) gene. The mammalian Tim genes are widely expressed in a variety of tissues; however, unlike Drosophila, mTim mRNA levels do not oscillate in the suprachiasmatic nucleus (SCN) or retina. Importantly, hTIM interacts with the Drosophila PERIOD (dPER) protein as well as the mouse PER1 and PER2 proteins in vitro. In Drosophila (S2) cells, hTIM and dPER interact and translocate into the nucleus. Finally, hTIM and mPER1 specifically inhibit CLOCK-BMAL1-induced transactivation of the mPer1 promoter. Taken together, these results demonstrate that mTim and hTIM are mammalian orthologs of timeless and provide a framework for a basic circadian autoregulatory loop in mammals.
Assuntos
Ritmo Circadiano/genética , Proteínas de Drosophila , Proteínas de Insetos/fisiologia , Proteínas Nucleares/metabolismo , Transativadores/genética , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Fatores de Transcrição ARNTL , Processamento Alternativo/genética , Sequência de Aminoácidos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Relógios Biológicos/genética , Proteínas CLOCK , Proteínas de Ciclo Celular , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Humanos Par 12/genética , Clonagem Molecular , Drosophila , Feminino , Humanos , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Proteínas Nucleares/fisiologia , Proteínas Circadianas Period , Polimorfismo Genético , RNA Mensageiro/biossíntese , Transativadores/antagonistas & inibidores , Fatores de Transcrição/metabolismoRESUMO
To determine the function of VGF, a secreted polypeptide that is synthesized by neurons, is abundant in the hypothalamus, and is regulated in the brain by electrical activity, injury, and the circadian clock, we generated knockout mice lacking Vgf. Homozygous mutants are small, hypermetabolic, hyperactive, and infertile, with markedly reduced leptin levels and fat stores and altered hypothalamic proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related peptide (AGRP) expression. Furthermore, VGF mRNA synthesis is induced in the hypothalamic arcuate nuclei of fasted normal mice. VGF therefore plays a critical role in the regulation of energy homeostasis, suggesting that the study of lean VGF mutant mice may provide insight into wasting disorders and, moreover, that pharmacological antagonism of VGF action(s) might constitute the basis for treatment of obesity.
Assuntos
Metabolismo Energético/fisiologia , Deleção de Genes , Neurônios/metabolismo , Proteínas/genética , Proteínas/metabolismo , Agressão/fisiologia , Animais , Núcleo Arqueado do Hipotálamo/química , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/metabolismo , Peso Corporal/fisiologia , Catecolaminas/metabolismo , Ritmo Circadiano/fisiologia , Jejum/fisiologia , Feminino , Fertilidade , Expressão Gênica/fisiologia , Gonadotropinas/metabolismo , Homeostase/fisiologia , Hibridização In Situ , Leptina , Masculino , Glândulas Mamárias Animais/química , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Crescimento Neural , Neurônios/química , Neuropeptídeos , Ovário/química , Ovário/metabolismo , Consumo de Oxigênio/fisiologia , Fenótipo , Hipófise/química , Hipófise/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , RNA Mensageiro/análise , Tireotropina/genéticaRESUMO
During the past year, our understanding of the cellular and molecular processes involved in the generation and control of circadian rhythms has advanced significantly. Progress has been made at the level of the circadian pacemaker mechanism itself, the input pathways that regulate the pacemaker, and the mechanisms by which the pacemaker regulates its various outputs. A common theme underlying all three of these processes is the involvement of transcriptional and translational control. This review is an updated and extended version of a review first published in Current Opinion in Neurobiology 1991, 1:556-561.
Assuntos
Ritmo Circadiano/genética , Regulação da Expressão Gênica , Grupos de População Animal/genética , Grupos de População Animal/fisiologia , Animais , Drosophila/genética , Drosophila/fisiologia , Proteínas de Drosophila , Modelos Genéticos , Proteínas Nucleares/fisiologia , Proteínas Circadianas Period , Fenômenos Fisiológicos Vegetais , Plantas/genética , Biossíntese de Proteínas , Núcleo Supraquiasmático/fisiologia , Fatores de Transcrição/fisiologia , Transcrição GênicaRESUMO
Much progress has been made during the past year in the molecular dissection of the circadian clock. Recently identified circadian genes in mouse, Drosophila, and cyanobacteria demonstrate the universal nature of negative feedback regulation as a circadian mechanism; furthermore, the mouse and Drosophila genes are structurally and functionally conserved. In addition, the discovery of brain-independent clocks promises to revolutionize the study of circadian biology.
Assuntos
Ritmo Circadiano/genética , Regulação da Expressão Gênica , Animais , Cianobactérias/genética , Cianobactérias/fisiologia , Drosophila/fisiologia , Mamíferos , Camundongos , Neurospora/genética , Neurospora/fisiologiaRESUMO
The suprachiasmatic nucleus (SCN) is the master circadian pacemaker in mammals, and one molecular regulator of circadian rhythms is the Clock gene. Here we studied the discharge patterns of SCN neurons isolated from Clock mutant mice. Long-term, multielectrode recordings showed that heterozygous Clock mutant neurons have lengthened periods and that homozygous Clock neurons are arrhythmic, paralleling the effects on locomotor activity in the animal. In addition, cells in dispersals expressed a wider range of periods and phase relationships than cells in explants. These results suggest that the Clock gene is required for circadian rhythmicity in individual SCN cells and that a mechanism within the SCN synchronizes neurons and restricts the range of expressed circadian periods.