scholarly journals Photoperiodic and clock regulation of the vitamin A pathway in the brain mediates seasonal responsiveness in the monarch butterfly

2019 ◽  
Vol 116 (50) ◽  
pp. 25214-25221 ◽  
Author(s):  
Samantha E. Iiams ◽  
Aldrin B. Lugena ◽  
Ying Zhang ◽  
Ashley N. Hayden ◽  
Christine Merlin
Keyword(s):  
Vitamin A ◽  
Circadian Clock ◽  
Environmental Changes ◽  
Clock Genes ◽  
Monarch Butterfly ◽  
Genetic Evidence ◽  
Mammalian Brain ◽  
Loss Of Function ◽  
Photoperiodic Responses ◽  
The Brain

Seasonal adaptation to changes in light:dark regimes (i.e., photoperiod) allows organisms living at temperate latitudes to anticipate environmental changes. In nearly all animals studied so far, the circadian system has been implicated in measurement and response to the photoperiod. In insects, genetic evidence further supports the involvement of several clock genes in photoperiodic responses. Yet, the key molecular pathways linking clock genes or the circadian clock to insect photoperiodic responses remain largely unknown. Here, we show that inactivating the clock in the North American monarch butterfly using loss-of-function mutants for the circadian activators CLOCK and BMAL1 and the circadian repressor CRYPTOCHROME 2 abolishes photoperiodic responses in reproductive output. Transcriptomic approaches in the brain of monarchs raised in long and short photoperiods, summer monarchs, and fall migrants revealed a molecular signature of seasonal-specific rhythmic gene expression that included several genes belonging to the vitamin A pathway. We found that the rhythmic expression of these genes was abolished in clock-deficient mutants, suggesting that the vitamin A pathway operates downstream of the circadian clock. Importantly, we showed that a CRISPR/Cas9-mediated loss-of-function mutation in the gene encoding the pathway’s rate-limiting enzyme, ninaB1, abolished photoperiod responsiveness independently of visual function in the compound eye and without affecting circadian rhythms. Together, these results provide genetic evidence that the clock-controlled vitamin A pathway mediates photoperiod responsiveness in an insect. Given previously reported seasonal changes associated with this pathway in the mammalian brain, our findings suggest an evolutionarily conserved function of vitamin A in animal photoperiodism.

scholarly journals Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

2021 ◽  
Vol 22 (2) ◽  
pp. 676
Author(s):  
Andy W. C. Man ◽  
Huige Li ◽  
Ning Xia
Keyword(s):  
Circadian Rhythm ◽  
Cardiovascular Diseases ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Therapeutic Target ◽  
Environmental Changes ◽  
Clock Genes ◽  
Vascular System ◽  
Peripheral Tissues ◽  
Inflammatory Processes

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the 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.

scholarly journals The Development and Decay of the Circadian Clock in Drosophila melanogaster

2019 ◽  
Vol 1 (4) ◽  
pp. 489-500
Author(s):  
Jia Zhao ◽  
Guy Warman ◽  
James Cheeseman
Keyword(s):  
Circadian Clock ◽  
Clock Genes ◽  
Firefly Luciferase ◽  
Whole Body ◽  
Drosophila Model ◽  
Central Clock ◽  
Development And Aging ◽  
Central Oscillator ◽  
The Brain ◽  
Insight Into

The way in which the circadian clock mechanism develops and decays throughout life is interesting for a number of reasons and may give us insight into the process of aging itself. The Drosophila model has been proven invaluable for the study of the circadian clock and development and aging. Here we review the evidence for how the Drosophila clock develops and changes throughout life, and present a new conceptual model based on the results of our recent work. Firefly luciferase lines faithfully report the output of known clock genes at the central clock level in the brain and peripherally throughout the whole body. Our results show that the clock is functioning in embryogenesis far earlier than previously thought. This central clock in the fly remains robust throughout the life of the animal and only degrades immediately prior to death. However, at the peripheral (non-central oscillator level) the clock shows weakened output as the animal ages, suggesting the possibility of the breakdown in the cohesion of the circadian network.

scholarly journals Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

2019 ◽  
Author(s):  
Wai Hoong Chang ◽  
Alvina G. Lai
Keyword(s):  
Circadian Clock ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
Clock Genes ◽  
Tumour Progression ◽  
Prognostic Significance ◽  
Integrated Approach ◽  
Loss Of Function ◽  
Gene Sets

The circadian clock governs a large variety of fundamentally important physiological processes in all three domains of life. Consequently, asynchrony in timekeeping mechanisms could give rise to cellular dysfunction underpinning many disease pathologies including human neoplasms. Yet, detailed pancancer evidence supporting this notion has been limited. In an integrated approach uniting genetic, transcriptomic and clinical data of 21 cancer types (n=18,484), we interrogated copy number and transcript profiles of 32 circadian clock genes to identify putative loss-of-function (ClockLoss) and gain-of-function (ClockGain) players. Kaplan-Meier, Cox regression and receiver operating characteristic analyses were employed to evaluate the prognostic significance of both gene sets. ClockLoss and ClockGain were associated with tumoursuppressing and tumour-promoting roles respectively. Downregulation of ClockLoss genes resulted in significant higher mortality rates in five cancer cohorts (n=2,914): bladder (P=0.027), glioma (P<0.0001), pan-kidney (P=0.011), clear cell renal cell (P<0.0001) and stomach (P=0.0007). In contrast, patients with high expression of oncogenic ClockGain genes had poorer survival outcomes (n=2,784): glioma (P<0.0001), pan-kidney (P=0.0034), clear cell renal cell (P=0.014), lung (P=0.046) and pancreas (P=0.0059). Both gene sets were independent of other clinicopathological features to permit further delineation of tumours within the same stage. Circadian reprogramming of tumour genomes resulted in activation of numerous oncogenic pathways including those associated with cancer stem cells, suggesting that the circadian clock may influence self-renewal mechanisms. Within the hypoxic tumour microenvironment, circadian dysregulation is exacerbated by tumour hypoxia in glioma, renal, lung and pancreatic cancers, resulting in additional death risks. Tumour suppressive ClockLoss genes were negatively correlated with hypoxia inducible factor-1A targets in glioma patients, providing a novel framework for investigating the hypoxia-clock signalling axis. Loss of timekeeping fidelity promotes tumour progression and influences clinical outcomes. ClockLoss and ClockGain may offer novel druggable targets for improving patient prognosis. Both gene sets can be used for patient stratification in adjuvant chronotherapy treatment. Emerging interactions between the circadian clock and hypoxia may be harnessed to achieve therapeutic advantage using hypoxia-modifying compounds in combination with first-line treatments.

scholarly journals Phytochromes measure photoperiod in Brachypodium

2019 ◽  
Author(s):  
Mingjun Gao ◽  
Feng Geng ◽  
Cornelia Klose ◽  
Anne-Marie Staudt ◽  
He Huang ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Conceptual Framework ◽  
Growth And Development ◽  
Clock Genes ◽  
Brachypodium Distachyon ◽  
Adaptive Trait ◽  
Long Day ◽  
Northern Latitudes ◽  
Photoperiodic Responses ◽  
Clock Protein

SummaryDaylength is a key seasonal cue for animals and plants. In cereals, photoperiodic responses are a major adaptive trait, and alleles of clock genes such as PHOTOPERIOD DEPENDENT1 (PPD1) and EARLY FLOWERING3 (ELF3) have been selected for in breeding barley and wheat for more northern latitudes (Faure et al., 2012; Turner, Beales, Faure, Dunford, & Laurie, 2005). How monocot plants sense photoperiod and integrate this information into growth and development is not well understood. We show that in Brachypodium distachyon, phytochrome C (phyC) acts as a molecular timer, directly communicating information to the circadian clock protein ELF3. In this way, ELF3 levels integrate night length information. ELF3 is a central regulator of photoperiodism in Brachypodium, and elf3 mutants display a constitutive long day transcriptome. Conversely, conditions that result in higher levels of ELF3 suppress long day responses. We are able to show that these effects are direct, as ELF3 and phyC occur in a common complex, and they associate with the promoters of a number of conserved regulators of photoperiodism, including PPD1. Consistent with observations in barley, we are able to show that PPD1 overexpression accelerates flowering in SD and is necessary for rapid flowering in response to LD. These findings provide a conceptual framework for understanding observations in the photoperiodic responses of key crops, including wheat, barley and rice.

scholarly journals Intermittent Hypoxia Alters the Circadian Expression of Clock Genes in Mouse Brain and Liver

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1627
Author(s):  
Bala S. C. Koritala ◽  
Yin Yeng Lee ◽  
Shweta S. Bhadri ◽  
Laetitia S. Gaspar ◽  
Corinne Stanforth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Intermittent Hypoxia ◽  
Clock Genes ◽  
The United States ◽  
Circadian Expression ◽  
Polymerase Chain ◽  
States Experience ◽  
The Impact ◽  
The Brain

At least one-third of adults in the United States experience intermittent hypoxia (IH) due to health or living conditions. The majority of these adults suffer with sleep breathing conditions and associated circadian rhythm disorders. The impact of IH on the circadian clock is not well characterized. In the current study, we used an IH mouse model to understand the impact of IH on the circadian gene expression of the canonical clock genes in the central (the brain) and peripheral (the liver) tissues. Gene expression was measured using a Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). CircaCompare was used to evaluate the differential rhythmicity between normoxia and IH. Our observations suggested that the circadian clock in the liver was less sensitive to IH compared to the circadian clock in the brain.

scholarly journals Oviposition-promoting pars intercerebralis neurons show period-dependent photoperiodic changes in their firing activity in the bean bug

2021 ◽  
Vol 118 (9) ◽  
pp. e2018823118
Author(s):  
Masaharu Hasebe ◽  
Sakiko Shiga
Keyword(s):  
Rna Interference ◽  
Circadian Clock ◽  
Ovarian Development ◽  
Clock Genes ◽  
Neuronal Response ◽  
Photoperiodic Response ◽  
Firing Activity ◽  
Pars Intercerebralis ◽  
Photoperiodic Responses ◽  
Bean Bug

Animals show photoperiodic responses in physiology and behavior to adapt to seasonal changes. Recent genetic analyses have demonstrated the significance of circadian clock genes in these responses. However, the importance of clock genes in photoperiodic responses at the cellular level and the physiological roles of the cellular responses are poorly understood. The bean bug Riptortus pedestris shows a clear photoperiodic response in its reproduction. In the bug, the pars intercerebralis (PI) is an important brain region for promoting oviposition. Here, we analyzed the role of the photoperiodic neuronal response and its relationship with clock genes, focusing on PI neurons. Large PI neurons exhibited photoperiodic firing changes, and high firing activities were primarily found under photoperiodic conditions suitable for oviposition. RNA interference-mediated knockdown of the clock gene period abolished the photoperiodic response in PI neurons, as well as the response in ovarian development. To clarify whether the photoperiodic response in the PI was dependent on ovarian development, we performed an ovariectomy experiment. Ovariectomy did not have significant effects on the firing activity of PI neurons. Finally, we identified the output molecules of the PI neurons and analyzed the relevance of the output signals in oviposition. PI neurons express multiple neuropeptides—insulin-like peptides and diuretic hormone 44—and RNA interference of these neuropeptides reduced oviposition. Our results suggest that oviposition-promoting peptidergic neurons in the PI exhibit a circadian clock-dependent photoperiodic firing response, which contributes to the photoperiodic promotion of oviposition.

scholarly journals Evidence for oscillating circadian clock genes in the copepod Calanus finmarchicus during the summer solstice in the high Arctic

2020 ◽  
Vol 16 (7) ◽  
pp. 20200257 ◽  
Author(s):  
Lukas Hüppe ◽  
Laura Payton ◽  
Kim Last ◽  
David Wilcockson ◽  
Elizaveta Ershova ◽  
...  
Keyword(s):  
Sea Ice ◽  
Circadian Clock ◽  
Environmental Changes ◽  
Clock Genes ◽  
High Arctic ◽  
Calanus Finmarchicus ◽  
The Arctic ◽  
Summer Solstice ◽  
Solar Altitude ◽  
Circadian Clock Genes

The circadian clock provides a mechanism for anticipating environmental cycles and is synchronized by temporal cues such as daily light/dark cycle or photoperiod. However, the Arctic environment is characterized by several months of Midnight Sun when the sun is continuously above the horizon and where sea ice further attenuates photoperiod. To test if the oscillations of circadian clock genes remain in synchrony with subtle environmental changes, we sampled the copepod Calanus finmarchicus, a key zooplankter in the north Atlantic, to determine in situ daily circadian clock gene expression near the summer solstice at a southern (74.5° N) sea ice-free and a northern (82.5° N) sea ice-covered station. Results revealed significant oscillation of genes at both stations, indicating the persistence of the clock at this time. While copepods from the southern station showed oscillations in the daily range, those from the northern station exhibited an increase in ultradian oscillations. We suggest that in C. finmarchicus , even small daily changes of solar altitude seem to be sufficient to entrain the circadian clock and propose that at very high latitudes, in under-ice ecosystems, tidal cues may be used as an additional entrainment cue.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

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