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1.
EMBO J ; 40(7): e106745, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33491228

RESUMO

Circadian rhythms are a pervasive property of mammalian cells, tissues and behaviour, ensuring physiological adaptation to solar time. Models of cellular timekeeping revolve around transcriptional feedback repression, whereby CLOCK and BMAL1 activate the expression of PERIOD (PER) and CRYPTOCHROME (CRY), which in turn repress CLOCK/BMAL1 activity. CRY proteins are therefore considered essential components of the cellular clock mechanism, supported by behavioural arrhythmicity of CRY-deficient (CKO) mice under constant conditions. Challenging this interpretation, we find locomotor rhythms in adult CKO mice under specific environmental conditions and circadian rhythms in cellular PER2 levels when CRY is absent. CRY-less oscillations are variable in their expression and have shorter periods than wild-type controls. Importantly, we find classic circadian hallmarks such as temperature compensation and period determination by CK1δ/ε activity to be maintained. In the absence of CRY-mediated feedback repression and rhythmic Per2 transcription, PER2 protein rhythms are sustained for several cycles, accompanied by circadian variation in protein stability. We suggest that, whereas circadian transcriptional feedback imparts robustness and functionality onto biological clocks, the core timekeeping mechanism is post-translational.


Assuntos
Ritmo Circadiano , Criptocromos/metabolismo , Animais , Células Cultivadas , Criptocromos/deficiência , Criptocromos/genética , Drosophila melanogaster , Feminino , Locomoção , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo
2.
Sci Rep ; 7: 40304, 2017 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-28084307

RESUMO

Sleep is a highly conserved and essential behaviour in many species, including the fruit fly Drosophila melanogaster. In the wild, sensory signalling encoding environmental information must be integrated with sleep drive to ensure that sleep is not initiated during detrimental conditions. However, the molecular and circuit mechanisms by which sleep timing is modulated by the environment are unclear. Here we introduce a novel behavioural paradigm to study this issue. We show that in male fruit flies, onset of the daytime siesta is delayed by ambient temperatures above 29 °C. We term this effect Prolonged Morning Wakefulness (PMW). We show that signalling through the TrpA1 thermo-sensor is required for PMW, and that TrpA1 specifically impacts siesta onset, but not night sleep onset, in response to elevated temperatures. We identify two critical TrpA1-expressing circuits and show that both contact DN1p clock neurons, the output of which is also required for PMW. Finally, we identify the circadian blue-light photoreceptor CRYPTOCHROME as a molecular regulator of PMW, and propose a model in which the Drosophila nervous system integrates information encoding temperature, light, and time to dynamically control when sleep is initiated. Our results provide a platform to investigate how environmental inputs co-ordinately regulate sleep plasticity.


Assuntos
Ritmo Circadiano/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Sono/genética , Canal de Cátion TRPA1/genética , Animais , Drosophila melanogaster/fisiologia , Humanos , Canais Iônicos , Luz , Modelos Animais , Atividade Motora/genética , Neurônios/metabolismo , Neurônios/fisiologia , Sono/fisiologia , Temperatura , Vigília/genética , Vigília/fisiologia
3.
PLoS One ; 11(1): e0146571, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26741981

RESUMO

Cryptochrome (CRY) is the primary photoreceptor of Drosophila's circadian clock. It resets the circadian clock by promoting light-induced degradation of the clock protein Timeless (TIM) in the proteasome. Under constant light, the clock stops because TIM is absent, and the flies become arrhythmic. In addition to TIM degradation, light also induces CRY degradation. This depends on the interaction of CRY with several proteins such as the E3 ubiquitin ligases Jetlag (JET) and Ramshackle (BRWD3). However, CRY can seemingly also be stabilized by interaction with the kinase Shaggy (SGG), the GSK-3 beta fly orthologue. Consequently, flies with SGG overexpression in certain dorsal clock neurons are reported to remain rhythmic under constant light. We were interested in the interaction between CRY, Ramshackle and SGG and started to perform protein interaction studies in S2 cells. To our surprise, we were not able to replicate the results, that SGG overexpression does stabilize CRY, neither in S2 cells nor in the relevant clock neurons. SGG rather does the contrary. Furthermore, flies with SGG overexpression in the dorsal clock neurons became arrhythmic as did wild-type flies. Nevertheless, we could reproduce the published interaction of SGG with TIM, since flies with SGG overexpression in the lateral clock neurons shortened their free-running period. We conclude that SGG does not directly interact with CRY but rather with TIM. Furthermore we could demonstrate, that an unspecific antibody explains the observed stabilization effects on CRY.


Assuntos
Criptocromos/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/enzimologia , Proteínas do Olho/metabolismo , Quinase 3 da Glicogênio Sintase/fisiologia , Animais , Linhagem Celular , Relógios Circadianos , Estabilidade Proteica , Proteólise
4.
Cell Rep ; 11(6): 866-874, 2015 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-25937282

RESUMO

G-protein-coupled receptors (GPCRs) are typically regarded as chemosensors that control cellular states in response to soluble extracellular cues. However, the modality of stimuli recognized through adhesion GPCR (aGPCR), the second largest class of the GPCR superfamily, is unresolved. Our study characterizes the Drosophila aGPCR Latrophilin/dCirl, a prototype member of this enigmatic receptor class. We show that dCirl shapes the perception of tactile, proprioceptive, and auditory stimuli through chordotonal neurons, the principal mechanosensors of Drosophila. dCirl sensitizes these neurons for the detection of mechanical stimulation by amplifying their input-output function. Our results indicate that aGPCR may generally process and modulate the perception of mechanical signals, linking these important stimuli to the sensory canon of the GPCR superfamily.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Mecanotransdução Celular , Receptores de Peptídeos/metabolismo , Estimulação Acústica , Alelos , Animais , Sequência de Bases , Adesão Celular , Cílios/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Fenômenos Eletrofisiológicos , Epistasia Genética , Engenharia Genética , Loci Gênicos , Larva/fisiologia , Locomoção , Dados de Sequência Molecular , Mutação/genética , Neurônios , Regiões Promotoras Genéticas/genética , Receptores de Peptídeos/genética , Reflexo de Sobressalto , Estresse Mecânico
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