Spontaneous Recovery of Circadian Organization in Mice Lacking a Core Component of the Molecular Clockwork

2021 ◽  
pp. 074873042110608
Author(s):  
Jonathan P. Riggle ◽  
Kenneth G. Onishi ◽  
Jharnae A. Love ◽  
Dana E. Beach ◽  
Irving Zucker ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Spontaneous Recovery ◽  
Clock Genes ◽  
Feedback Loops ◽  
Constant Darkness ◽  
Core Component ◽  
Period 2 ◽  
Circadian Organization ◽  
Circadian Clock Genes ◽  
Free Running

Circadian rhythms are generated by interlocked transcriptional-translational feedback loops of circadian clock genes and their protein products. Mice homozygous for a functional deletion in the Period-2 gene ( Per2m/m mice) exhibit short free-running circadian periods and eventually lose behavioral circadian rhythmicity in constant darkness (DD). We investigated Per2m/m mice in DD for several months and identified a categorical sex difference in the dependence on Per2 for maintenance of circadian rhythms. Nearly all female Per2m/m mice became circadian arrhythmic in DD, whereas free-running rhythms persisted in 37% of males. Remarkably, with extended testing, Per2m/m mice did not remain arrhythmic in DD, but after varying intervals spontaneously recovered robust, free-running circadian rhythms, with periods shorter than those expressed prior to arrhythmia. Spontaneous recovery was strikingly sex-biased, occurring in 95% of females and 33% of males. Castration in adulthood resulted in male Per2m/m mice exhibiting female-like levels of arrhythmia in DD, but did not affect spontaneous recovery. The circadian pacemaker of many gonad-intact males, but not females, can persist in DD for long intervals without a functional PER2 protein; their circadian clocks may be in an unstable equilibrium, incapable of sustaining persistent coherent circadian organization, resulting in transient cycles of circadian organization and arrhythmia.

scholarly journals Shared Components of the FRQ-Less Oscillator and TOR Pathway Maintain Rhythmicity in Neurospora

2021 ◽  
pp. 074873042199994
Author(s):  
Rosa Eskandari ◽  
Lalanthi Ratnayake ◽  
Patricia L. Lakin-Thomas
Keyword(s):  
Circadian Rhythms ◽  
Clock Genes ◽  
Nutrient Sensing ◽  
Mass Spectrometry Analysis ◽  
Growth Responses ◽  
Tor Pathway ◽  
Spectrometry Analysis ◽  
Binding Partner ◽  
Binding Partners ◽  
Free Running

Molecular models for the endogenous oscillators that drive circadian rhythms in eukaryotes center on rhythmic transcription/translation of a small number of “clock genes.” Although substantial evidence supports the concept that negative and positive transcription/translation feedback loops (TTFLs) are responsible for regulating the expression of these clock genes, certain rhythms in the filamentous fungus Neurospora crassa continue even when clock genes ( frq, wc-1, and wc-2) are not rhythmically expressed. Identification of the rhythmic processes operating outside of the TTFL has been a major unresolved area in circadian biology. Our lab previously identified a mutation ( vta) that abolishes FRQ-less rhythmicity of the conidiation rhythm and also affects rhythmicity when FRQ is functional. Further studies identified the vta gene product as a component of the TOR (Target of Rapamycin) nutrient-sensing pathway that is conserved in eukaryotes. We now report the discovery of TOR pathway components including GTR2 (homologous to the yeast protein Gtr2, and RAG C/D in mammals) as binding partners of VTA through co-immunoprecipitation (IP) and mass spectrometry analysis using a VTA-FLAG strain. Reciprocal IP with GTR2-FLAG found VTA as a binding partner. A Δ gtr2 strain was deficient in growth responses to amino acids. Free-running conidiation rhythms in a FRQ-less strain were abolished in Δ gtr2. Entrainment of a FRQ-less strain to cycles of heat pulses demonstrated that Δ gtr2 is defective in entrainment. In all of these assays, Δ gtr2 is similar to Δ vta. In addition, expression of GTR2 protein was found to be rhythmic across two circadian cycles, and functional VTA was required for GTR2 rhythmicity. FRQ protein exhibited the expected rhythm in the presence of GTR2 but the rhythmic level of FRQ dampened in the absence of GTR2. These results establish association of VTA with GTR2, and their role in maintaining functional circadian rhythms through the TOR pathway.

Organization of rat circadian rhythms during daily infusion of melatonin or S20098, a melatonin agonist

1999 ◽  
Vol 277 (3) ◽  
pp. R812-R828 ◽  
Author(s):  
B. Pitrosky ◽  
R. Kirsch ◽  
A. Malan ◽  
E. Mocaer ◽  
P. Pevet
Keyword(s):  
Body Temperature ◽  
Circadian Rhythms ◽  
Phase Response Curve ◽  
Constant Darkness ◽  
Time Interval ◽  
General Activity ◽  
Activity Peak ◽  
Free Running ◽  
Wheel Activity ◽  
Free Running Period

Daily administration of melatonin or S20098, a melatonin agonist, is known to entrain the free-running circadian rhythms of rats. The effects of the duration of administration on entrainment were studied. The animals demonstrated free-running circadian rhythms (running-wheel activity, body temperature, general activity) in constant darkness. Daily infusions of melatonin or S20098 for 1, 8, or 16 h entrained the circadian rhythms to 24 h. Two daily infusions of 1 h (separated by 8 h) entrained the activity peak within the shorter time interval. The entraining properties of melatonin and S20098 were similar and were affected neither by pinealectomy nor by infusion of 1- or 8-h duration. However, with 16-h infusion, less than half of the animals became entrained. Once entrained, the phase angle between the onset of infusion and the rhythms (onset of activity or acrophase of body temperature) increased with the duration of infusion. Before entrainment, the free-running period increased with the duration of infusion, an effect that was not predictable from the phase response curve.

scholarly journals Modulatory Effects of Circadian Rhythms in the Lung Adenocarcinoma Tumor Microenvironment

2021 ◽  
Author(s):  
Qianzhun Huang ◽  
Xiaoyang Su ◽  
Ning Fang ◽  
Jian Huang
Keyword(s):  
Tumor Microenvironment ◽  
Circadian Rhythms ◽  
Lung Adenocarcinoma ◽  
Circadian Clock ◽  
Drug Sensitivity ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Functional Enrichment ◽  
Expression Levels ◽  
Circadian Clock Genes

Abstract Background: Dysregulated circadian dynamic balance is strongly associated with cancer development. However, biological functions of circadian rhythms in lung adenocarcinoma (LUAD) have not been elucidated. This study aimed at valuating the modulatory effects of circadian rhythms in the LUAD tumor microenvironment.Methods: Multiple open-source bioinformatics research platforms are used to comprehensively elucidate the expression level, prognosis, potential biological function, drug sensitivity, and immune microenvironment of circadian clock genes in LUAD.Results: Most circadian clock genes in LUAD are dysregulated and are strongly correlated with patient prognosis, and missense mutations at splicing sites of these genes. Besides, these genes are closely associated with some well-known cancer-related marker pathways, which are mainly involved in the inhibition of the Apoptosis, Cell cycle, and DNA Damage Response Pathway. Furthermore, functional enrichment analysis revealedthat circadian clock genes regulate transcription factor activities and circadian rhythms in LUAD tissues. As for drug sensitivity, high expression of CLOCK, CRY1, and NR1D2 as well as suppressedPER2 and CRY2 expression levels are associated with drug resistance. The expression levels of circadian clock genes in LUAD correlate with immune infiltration and are involved in the regulation of immunosuppression.Conclusions: Our multi-omics analysis provides a more comprehensive understanding of the molecular mechanisms of the circadian clock genes in LUAD and provides new insights for a more precise screening of prognostic biomarkers and immunotherapy.

scholarly journals Free-running circadian breathing rhythms are eliminated by suprachiasmatic nucleus lesion

2020 ◽  
Vol 129 (1) ◽  
pp. 49-57
Author(s):  
Benton S. Purnell ◽  
Gordon F. Buchanan
Keyword(s):  
Sleep Apnea ◽  
Circadian Rhythms ◽  
Suprachiasmatic Nucleus ◽  
Time Of Day ◽  
Sudden Unexpected Death ◽  
Constant Darkness ◽  
Unexpected Death ◽  
Treatment And Prevention ◽  
Free Running

It has long been appreciated that breathing is altered by time of day. This study demonstrates that rhythmicity in breathing persists in constant darkness but is dependent on the suprachiasmatic nucleus in the hypothalamus. Understanding circadian rhythms in breathing may be important for the treatment and prevention of diseases such as sleep apnea and sudden unexpected death in epilepsy.

Maternal-fetal communication of circadian phase in a precocious rodent, the spiny mouse

1987 ◽  
Vol 253 (4) ◽  
pp. E401-E409
Author(s):  
D. R. Weaver ◽  
S. M. Reppert
Keyword(s):  
Circadian Rhythms ◽  
Postnatal Period ◽  
Spiny Mouse ◽  
Constant Darkness ◽  
Suprachiasmatic Nuclei ◽  
Maternal Influences ◽  
Circadian Phase ◽  
Environmental Light ◽  
Running Activity ◽  
Free Running

The development of circadian rhythms was examined in a precocious rodent species, the spiny mouse. Spiny mouse pups born and reared in constant darkness expressed robust circadian rhythms in locomotor activity as early as day 5 of life. Free-running activity rhythms of pups born and reared in constant darkness were coordinated with the dam on the day of birth. Postnatal maternal influences on pup rhythmicity are minimal in this species, as pups fostered on the day of birth to dams whose circadian phases were opposite to the pups' original dams were coordinated with their original dams on the day of birth. Studies using 2-deoxy-D-[1-14C]-glucose autoradiography showed that there were synchronous (coordinated) rhythms in metabolic activity in the maternal and fetal suprachiasmatic nuclei, directly demonstrating prenatal coordination of maternal and fetal rhythmicity. Maternal-fetal coordination of circadian phase was not the result of direct entrainment of the fetuses to the environmental light-dark cycle. These results demonstrate that there is prenatal communication of circadian phase in this precocious species, without demonstrable postnatal maternal influences on pup circadian rhythmicity. Spiny mice therefore represent an important animal model in which circadian rhythms in the postnatal period can be used to precisely assess prenatal influences on circadian phase.

Abolished Daily Expression Patterns of SIRT1, SIRT2, and SIRT5 in Human Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4613-4613
Author(s):  
Ming-Yu Yang ◽  
Pai-Mei Lin ◽  
Jui-Feng Hsu ◽  
Wen-Chi Yang ◽  
Yi-Chang Liu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Myeloid Leukemia ◽  
Clock Genes ◽  
Expression Patterns ◽  
Healthy Individuals ◽  
Daily Pattern ◽  
Genes Expression ◽  
Circadian Clock Genes

Abstract Abstract 4613 Circadian rhythms regulate various functions of human body and disruption of circadian rhythm has been associated with cancer development and tumor progression. Circadian clock genes use transcriptional-translational feedback loops to control circadian rhythms. Many transcriptional regulators are histone acetyltransferases (HAT) or histone deacetylases (HDAC). As clock function and integration of inputs rely on transcriptional regulation, it is possible that chromatin is remodeled during circadian cycles and in response to signals that regulate the clock. SIRT1 (sirtuin 1) is a HDAC that has recently been identified as a crucial modulator of the circadian clock machinery. To date, at least 7 SIRT genes (SIRT1–7) have been identified. In our previous report we have demonstrated the daily expression patterns of PER1, PER2, PER3, CRY1, CRY2, and CKIe in peripheral blood (PB) of healthy individuals were abolished in chronic myeloid leukemia (CML) patients and partial recoveries of daily patterns were observed in CML patients with complete cytogenetic response (CCyR) and major molecular response (MMR) post-imatinib treatment [J Biol Rhythms 2011]. In this study we further investigated the expression profiles of the 7 SIRT genes (SIRT1–7) in PB total leukocytes from 49 CML and 22 healthy volunteers. Collection of PB was carried out at four time points: 2000 h, 0200 h, 0800 h, and 1400 h, respectively. In PB total leukocytes of healthy individuals, the daily pattern of SIRT1 (p < 0.01) and SIRT5 (p < 0.05) expression level peaked at 0200 h, and SIRT2 (p < 0.01) peaked at 0800 h. Daily pattern expression of these 3 genes was abolished in newly diagnosed pre-imatinib mesylate treated and blast crisis-phase CML patients. Partial daily patterns of gene expression recoveries were observed in CML patients with CCyR and MMR. In some serial monitored individual patients, the recoveries of oscillations of SIRT1, 2, and 5 genes expression accompanied with the disappearance of BCR-ABL transcripts were also noted. The expression of SIRT3, 6, and 7 did not show a time-dependent variation among the healthy and CML patients. SIRT4 expression was undetectable both in the healthy and CML patients. Updated in vitro study results of the regulation of SIRT1, 2, and 5 genes on circadian clock genes expression will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Neuron-specific knockouts indicate the importance of network communication to Drosophila rhythmicity

2019 ◽  
Author(s):  
M Schlichting ◽  
MM Diaz ◽  
J Xin ◽  
M Rosbash
Keyword(s):  
Gene Expression ◽  
Circadian Rhythms ◽  
Intercellular Communication ◽  
Clock Gene ◽  
Feedback Loops ◽  
Neuronal Firing ◽  
Network Communication ◽  
Constant Darkness ◽  
Circadian Period ◽  
Clock Gene Expression

AbstractAnimal circadian rhythms persist in constant darkness and are driven by intracellular transcription-translation feedback loops. Although these cellular oscillators communicate, isolated mammalian cellular clocks continue to tick away in darkness without intercellular communication. To investigate these issues in Drosophila, we assayed behavior as well as molecular rhythms within individual brain clock neurons while blocking communication within the ca. 150 neuron clock network. We also generated CRISPR-mediated neuron-specific circadian clock knockouts. The results point to two key clock neuron groups: loss of the clock within both regions but neither one alone has a strong behavioral phenotype in darkness; communication between these regions also contributes to circadian period determination. Under these dark conditions, the clock within one region persists without network communication. The clock within the famous PDF-expressing s-LNv neurons however was strongly dependent on network communication, likely because clock gene expression within these vulnerable sLNvs depends on neuronal firing or light.

scholarly journals Weak Coupling Between Intracellular Feedback Loops Explains Dissociation of Clock Gene Dynamics

2019 ◽  
Author(s):  
Christoph Schmal ◽  
Daisuke Ono ◽  
Jihwan Myung ◽  
J. Patrick Pett ◽  
Sato Honma ◽  
...  
Keyword(s):  
Single Cell ◽  
Clock Genes ◽  
Experimental Studies ◽  
Feedback Loops ◽  
Light Pulses ◽  
Negative Feedback Loops ◽  
Medium Exchange ◽  
A Cell ◽  
Free Running ◽  
Underlying Mechanisms

Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described in recent experimental studies that applied various perturbations such as slice preparations, light pulses, jet-lag, and culture medium exchange. In this paper, we provide evidence that this "presumably transient" dissociation of circadian gene expression oscillations may occur at the single-cell level. Conceptual and detailed mechanistic mathematical modeling suggests that such dissociation is due to a weak interaction between multiple feedback loops present within a single cell. The dissociable loops provide insights into underlying mechanisms and general design principles of the molecular circadian clock.

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.

Daily exposure to a running wheel entrains circadian rhythms in mice in parallel with development of an increase in spontaneous movement prior to running-wheel access

2013 ◽  
Vol 305 (11) ◽  
pp. R1367-R1375 ◽  
Author(s):  
Yujiro Yamanaka ◽  
Sato Honma ◽  
Ken-ichi Honma
Keyword(s):  
Circadian Rhythms ◽  
Fixed Time ◽  
Time Of Day ◽  
Constant Darkness ◽  
Spontaneous Movement ◽  
Running Wheel ◽  
Daily Exposure ◽  
Free Running ◽  
Nonphotic Entrainment ◽  
Circadian Behavior

Entrainment of circadian behavior rhythms by daily exposure to a running wheel was examined in mice under constant darkness. Spontaneous movement was individually monitored for more than 6 mo by a thermal sensor. After establishment of steady-state free running, mice were placed in a different cage equipped with a running-wheel for 3 h once per day at 6 AM. The daily exchange was continued for 80 days. The number of wheel revolutions during exposure to the running wheel was also measured simultaneously with spontaneous movement. In 13 out of 17 mice, circadian behavior rhythm was entrained by daily wheel exposure, showing a period indistinguishable from 24 h. The entrainment occurred in parallel with an increase in spontaneous movement immediately prior to the daily wheel exposure. A similar preexposure increase was observed in only one of four nonentrained mice. The preexposure increase appeared in 19.5 days on average after the start of daily wheel exposure and persisted for 36 days on average after the termination of the exposure schedule. The preexposure increase was detected only when daily wheel exposure came into the activity phase of the circadian behavior rhythm, which was accompanied by an increase in the number of wheel revolutions. These findings indicate that a novel oscillation with a circadian period is induced in mice by daily exposure to a running wheel at a fixed time of day and suggest that the oscillation is involved in the nonphotic entrainment of circadian rhythms in spontaneous movement.

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