scholarly journals ASK family kinases mediate cellular stress and redox signaling to circadian clock

2018 ◽  
Vol 115 (14) ◽  
pp. 3646-3651 ◽  
Author(s):  
Kiyomichi Imamura ◽  
Hikari Yoshitane ◽  
Kazuki Hattori ◽  
Mitsuo Yamaguchi ◽  
Kento Yoshida ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Cultured Cells ◽  
Clock Genes ◽  
Cellular Stress ◽  
Underlying Mechanism ◽  
Circadian Period ◽  
Redox States ◽  
Rhythmic Expression ◽  
Physiological Impact ◽  
Intracellular Redox

Daily rhythms of behaviors and physiologies are generated by the circadian clock, which is composed of clock genes and the encoded proteins forming transcriptional/translational feedback loops (TTFLs). The circadian clock is a self-sustained oscillator and flexibly responds to various time cues to synchronize with environmental 24-h cycles. However, the key molecule that transmits cellular stress to the circadian clockwork is unknown. Here we identified apoptosis signal-regulating kinase (ASK), a member of the MAPKKK family, as an essential mediator determining the circadian period and phase of cultured cells in response to osmotic changes of the medium. The physiological impact of ASK signaling was demonstrated by a response of the clock to changes in intracellular redox states. Intriguingly, the TTFLs drive rhythmic expression of Ask genes, indicating ASK-mediated association of the TTFLs with intracellular redox. In behavioral analysis, Ask1, Ask2, and Ask3 triple-KO mice exhibited compromised light responses of the circadian period and phase in their activity rhythms. LC-MS/MS–based proteomic analysis identified a series of ASK-dependent and osmotic stress-responsive phosphorylations of proteins, among which CLOCK, a key component of the molecular clockwork, was phosphorylated at Thr843 or Ser845 in the carboxyl-terminal region. These findings reveal the ASK-dependent stress response as an underlying mechanism of circadian clock flexibility.

Achilles-Mediated and Sex-Specific Regulation of Circadian mRNA Rhythms in Drosophila

2019 ◽  
Vol 34 (2) ◽  
pp. 131-143 ◽  
Author(s):  
Jiajia Li ◽  
Renee Yin Yu ◽  
Farida Emran ◽  
Brian E. Chen ◽  
Michael E. Hughes
Keyword(s):  
Circadian Clock ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Clock Genes ◽  
Peripheral Tissues ◽  
Knock Down ◽  
Rhythmic Expression ◽  
The Core ◽  
Physiological Processes ◽  
Specific Regulation

The circadian clock is an evolutionarily conserved mechanism that generates the rhythmic expression of downstream genes. The core circadian clock drives the expression of clock-controlled genes, which in turn play critical roles in carrying out many rhythmic physiological processes. Nevertheless, the molecular mechanisms by which clock output genes orchestrate rhythmic signals from the brain to peripheral tissues are largely unknown. Here we explored the role of one rhythmic gene, Achilles, in regulating the rhythmic transcriptome in the fly head. Achilles is a clock-controlled gene in Drosophila that encodes a putative RNA-binding protein. Achilles expression is found in neurons throughout the fly brain using fluorescence in situ hybridization (FISH), and legacy data suggest it is not expressed in core clock neurons. Together, these observations argue against a role for Achilles in regulating the core clock. To assess its impact on circadian mRNA rhythms, we performed RNA sequencing (RNAseq) to compare the rhythmic transcriptomes of control flies and those with diminished Achilles expression in all neurons. Consistent with previous studies, we observe dramatic upregulation of immune response genes upon knock-down of Achilles. Furthermore, many circadian mRNAs lose their rhythmicity in Achilles knock-down flies, suggesting that a subset of the rhythmic transcriptome is regulated either directly or indirectly by Achilles. These Achilles-mediated rhythms are observed in genes involved in immune function and in neuronal signaling, including Prosap, Nemy and Jhl-21. A comparison of RNAseq data from control flies reveals that only 42.7% of clock-controlled genes in the fly brain are rhythmic in both males and females. As mRNA rhythms of core clock genes are largely invariant between the sexes, this observation suggests that sex-specific mechanisms are an important, and heretofore under-appreciated, regulator of the rhythmic transcriptome.

scholarly journals Rhythmic expression of circadian clock genes in the preovulatory ovarian follicles of the laying hen

PLoS ONE ◽  
2017 ◽  
Vol 12 (6) ◽  
pp. e0179019 ◽  
Author(s):  
Zhichao Zhang ◽  
Shuang Lai ◽  
Yagang Wang ◽  
Liang Li ◽  
Huadong Yin ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Clock Genes ◽  
Ovarian Follicles ◽  
Laying Hen ◽  
Rhythmic Expression ◽  
Circadian Clock Genes

Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: A possible mechanism of chemotherapy-induced circadian rhythm disturbances

2008 ◽  
Vol 75 (8) ◽  
pp. 1616-1622 ◽  
Author(s):  
Hideyuki Terazono ◽  
Ahmed Hamdan ◽  
Naoya Matsunaga ◽  
Naoto Hayasaka ◽  
Hiroaki Kaji ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Clock Genes ◽  
Rhythmic Expression ◽  
Circadian Clock Genes

scholarly journals Roles of Neuropeptides, VIP and AVP, in the Mammalian Central Circadian Clock

2021 ◽  
Vol 15 ◽  
Author(s):  
Daisuke Ono ◽  
Ken-ichi Honma ◽  
Sato Honma
Keyword(s):  
Transcription Factors ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Cellular Networks ◽  
Clock Genes ◽  
Circadian System ◽  
Developmental Changes ◽  
Circadian Period ◽  
Functional Roles ◽  
Environmental Light

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Individual SCN cells exhibit intrinsic oscillations, and their circadian period and robustness are different cell by cell in the absence of cellular coupling, indicating that cellular coupling is important for coherent circadian rhythms in the SCN. Several neuropeptides such as arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) are expressed in the SCN, where these neuropeptides function as synchronizers and are important for entrainment to environmental light and for determining the circadian period. These neuropeptides are also related to developmental changes of the circadian system of the SCN. Transcription factors are required for the formation of neuropeptide-related neuronal networks. Although VIP is critical for synchrony of circadian rhythms in the neonatal SCN, it is not required for synchrony in the embryonic SCN. During postnatal development, the clock genes cryptochrome (Cry)1 and Cry2 are involved in the maturation of cellular networks, and AVP is involved in SCN networks. This mini-review focuses on the functional roles of neuropeptides in the SCN based on recent findings in the literature.

scholarly journals Period 2: A Regulator of Multiple Tissue-Specific Circadian Functions

2021 ◽  
Vol 14 ◽  
Author(s):  
Gennaro Ruggiero ◽  
Zohar Ben-Moshe Livne ◽  
Yair Wexler ◽  
Nathalie Geyer ◽  
Daniela Vallone ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Clock Genes ◽  
Central Element ◽  
Light Sensitivity ◽  
Loss Of Function ◽  
Tissue Specific ◽  
Rhythmic Expression ◽  
Period 2 ◽  
Circadian Clock Genes

The zebrafish represents a powerful model for exploring how light regulates the circadian clock due to the direct light sensitivity of its peripheral clocks, a property that is retained even in organ cultures as well as zebrafish-derived cell lines. Light-inducible expression of the per2 clock gene has been predicted to play a vital function in relaying light information to the core circadian clock mechanism in many organisms, including zebrafish. To directly test the contribution of per2 to circadian clock function in zebrafish, we have generated a loss-of-function per2 gene mutation. Our results reveal a tissue-specific role for the per2 gene in maintaining rhythmic expression of circadian clock genes, as well as clock-controlled genes, and an impact on the rhythmic behavior of intact zebrafish larvae. Furthermore, we demonstrate that disruption of the per2 gene impacts on the circadian regulation of the cell cycle in vivo. Based on these results, we hypothesize that in addition to serving as a central element of the light input pathway to the circadian clock, per2 acts as circadian regulator of tissue-specific physiological functions in zebrafish.

Circadian clock regulates granulosa cell autophagy through NR1D1-mediated inhibition of ATG5

2021 ◽  
Author(s):  
Jing Zhang ◽  
Lijia Zhao ◽  
Yating Li ◽  
Hao Dong ◽  
Haisen Zhang ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Clock Genes ◽  
Expression Patterns ◽  
Current Data ◽  
Orphan Receptor ◽  
Luciferase Reporter ◽  
Mobility Shift ◽  
Rhythmic Expression ◽  
Clock System ◽  
Circadian Clock Genes

Autophagy of granulosa cells (GCs) is involved in follicular atresia, which occurs repeatedly during the ovarian development cycle. Several circadian clock genes are rhythmically expressed in both rodent ovarian tissues and GCs. Nuclear receptor subfamily 1 group D member 1 (NR1D1), an important component of the circadian clock system, is involved in the autophagy process through the regulation of autophagy-related genes. However, there are no reports illustrating the role of the circadian clock system in mouse GC autophagy. In the present study, we found that core circadian clock genes (Bmal1, Per2, Nr1d1, and Dbp) and an autophagy-related gene (Atg5) exhibited rhythmic expression patterns across 24 h in mouse ovaries and primary GCs. Treatment with SR9009, an agonist of NR1D1, significantly reduced the expression of Bmal1, Per2, and Dbp in mouse GCs. ATG5 expression was significantly attenuated by SR9009 treatment in mouse GCs. Conversely, Nr1d1 knockdown increased ATG5 expression in mouse GCs. Decreased NR1D1 expression at both the mRNA and protein levels was detected in the ovaries of Bmal1-/- mice, along with elevated expression of ATG5. Dual-luciferase reporter assay and electrophoretic mobility shift assay showed that NR1D1 inhibited Atg5 transcription by binding to two putative retinoic acid-related orphan receptor response elements within the promoter. In addition, rapamycin-induced autophagy and ATG5 expression were partially reversed by SR9009 treatment in mouse GCs. Taken together, our current data demonstrated that the circadian clock regulates GC autophagy through NR1D1-mediated inhibition of ATG5 expression, and thus, plays a role in maintaining autophagy homeostasis in GCs.

LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver

2013 ◽  
Vol 52 (2) ◽  
pp. 133-143 ◽  
Author(s):  
Feng Wang ◽  
Xianfeng Zhang ◽  
Jiqiu Wang ◽  
Maopei Chen ◽  
Nengguang Fan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Clock Genes ◽  
Plasma Cholesterol ◽  
Plasma Lipid ◽  
Microsomal Triglyceride Transfer Protein ◽  
Underlying Mechanism ◽  
Transcriptional Level ◽  
Cholesterol Levels

The circadian clock plays an important role in the liver by regulating the major aspects of energy metabolism. Currently, it is assumed that the circadian clock regulates metabolism mostly by regulating the expression of liver enzymes at the transcriptional level, but the underlying mechanism is not well understood. In this study, we showed that Lgr4 homozygous mutant (Lgr4m/m) mice showed alteration in the rhythms of the respiratory exchange ratio. We further detected impaired plasma triglyceride rhythms in Lgr4m/m mice. Although no significant changes in plasma cholesterol rhythms were observed in the Lgr4m/m mice, their cholesterol levels were obviously lower. This phenotype was further confirmed in the context of ob/ob mice, in which lack of LGR4 dampened circadian rhythms of triglyceride. We next demonstrated that Lgr4 expression exhibited circadian rhythms in the liver tissue and primary hepatocytes in mice, but we did not detect changes in the expression levels or circadian rhythms of classic clock genes, such as Clock, Bmal1 (Arntl), Pers, Rev-erbs, and Crys, in Lgr4m/m mice compared with their littermates. Among the genes related to the lipid metabolism, we found that the diurnal expression pattern of the Mttp gene, which plays an important role in the regulation of plasma lipid levels, was impaired in Lgr4m/m mice and primary Lgr4m/m hepatocytes. Taken together, our results demonstrate that LGR4 plays an important role in the regulation of plasma lipid rhythms, partially through regulating the expression of microsomal triglyceride transfer protein. These data provide a possible link between the peripheral circadian clock and lipid metabolism.

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