scholarly journals Clock gene expression in gravid uterus and extra-embryonic tissues during late gestation in the mouse

2010 ◽  
Vol 22 (5) ◽  
pp. 743 ◽  
Author(s):  
Christine K. Ratajczak ◽  
Erik D. Herzog ◽  
Louis J. Muglia
Keyword(s):  
Molecular Clock ◽  
Clock Genes ◽  
Circadian Rhythmicity ◽  
Late Gestation ◽  
Gravid Uterus ◽  
Fetal Membranes ◽  
Molecular Clocks ◽  
Potential Contribution ◽  
Rhythmic Expression ◽  
Clock Gene Expression

Evidence in humans and rodents suggests the importance of circadian rhythmicity in parturition. A molecular clock underlies the generation of circadian rhythmicity. While this molecular clock has been identified in numerous tissues, the expression and regulation of clock genes in tissues relevant to parturition is largely undefined. Here, the expression and regulation of the clock genes Bmal1, Clock, cryptochrome (Cry1/2) and period (Per1/2) was examined in the murine gravid uterus, placenta and fetal membranes during late gestation. All clock genes examined were expressed in the tissues of interest throughout the last third of gestation. Upregulation of a subset of these clock genes was observed in each of these tissues in the final two days of gestation. Oscillating expression of mRNA for a subset of the examined clock genes was detected in the gravid uterus, placenta and fetal membranes. Furthermore, bioluminescence recording on explants from gravid Per2::luciferase mice indicated rhythmic expression of PER2 protein in these tissues. These data demonstrate expression and rhythmicity of clock genes in tissues relevant to parturition indicating a potential contribution of peripheral molecular clocks to this process.

scholarly journals Pregnancy-induced changes in the circadian expression of hepatic clock genes: implications for maternal glucose homeostasis

2016 ◽  
Vol 311 (3) ◽  
pp. E575-E586 ◽  
Author(s):  
Michaela D. Wharfe ◽  
Caitlin S. Wyrwoll ◽  
Brendan J. Waddell ◽  
Peter J. Mark
Keyword(s):  
Clock Genes ◽  
Circadian Variation ◽  
Late Gestation ◽  
Hepatic Expression ◽  
Rhythmic Expression ◽  
Circadian Expression ◽  
Clock Gene Expression ◽  
Maternal Adaptation ◽  
Near Term ◽  
In Pregnancy

Adaptations in maternal carbohydrate metabolism are particularly important in pregnancy because glucose is the principal energy substrate used by the fetus. As metabolic homeostasis is intricately linked to the circadian system via the rhythmic expression of clock genes, it is likely that metabolic adaptations during pregnancy also involve shifts in maternal circadian function. We hypothesized that maternal adaptation in pregnancy involves changes in the hepatic expression of clock genes, which drive downstream shifts in circadian expression of glucoregulatory genes. Maternal liver and plasma ( n = 6–8/group) were collected across 24-h periods (0800, 1200, 1600, 2000, 0000, 0400) from C57Bl/6J mice under isoflurane-nitrous oxide anesthesia prior to and on days 6, 10, 14 and 18 of pregnancy (term = day 19). Hepatic expression of clock genes and glucoregulatory genes was determined by RT-qPCR. Hepatic clock gene expression was substantially altered across pregnancy, most notably in late gestation when the circadian rhythmicity of several clock genes was attenuated (≤64% reduced amplitude on day 18). These changes were associated with a similar decline in rhythmicity of the key glucoregulatory genes Pck1, G6Pase, and Gk, and by day 18, Pck1 was no longer rhythmic. Overall, our data show marked adaptations in the liver clock during mouse pregnancy, changes that may contribute to the altered circadian variation in glucoregulatory genes near term. We propose that the observed reduction of daily oscillations in glucose metabolism ensure a sustained supply of glucose to meet the high demands of fetal growth.

P–372 Maternal circadian disruption is associated with impaired rhythmic expression of molecular clock genes and IUGR during placenta development in mice

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
N I Bektas ◽  
G Akcay ◽  
N Derin ◽  
D Adiguzel ◽  
C Celik-Ozenci
Keyword(s):  
Circadian Rhythm ◽  
Locomotor Activity ◽  
Molecular Clock ◽  
Clock Genes ◽  
Weight Ratio ◽  
Circadian Disruption ◽  
Control Group ◽  
Shift Workers ◽  
Rhythmic Expression ◽  
Registration Number

Abstract Study question Are molecular clock genes (MCGs) expressed rhythmically in mouse placenta, and whether maternal circadian rhythm disruption (MCRD) is associated with intrauterine growth retardation (IUGR) through disturbing rhythmic expression of MCGs? Summary answer Maternal circadian disruption causes impaired rhythmic expression of MCGs (Bmal1, Clock, Npas2, Per1, Per2, Per3, Cry1, and Cry2) and IUGR during placenta development in mice. What is known already The world economy is based on a 24/7 society and shift work or jet travel across time zones disrupts circadian rhythm in pregnant women. Evidence indicates that gestational chrono-disruption results in IUGR. Mature mouse and human placenta express MCGs. There is no information in the literature on whether the MCG expression in the placenta is rhythmic or not and whether the rhythmic expression of MCGs is impaired due to MCRD during pregnancy. Also, it is not known whether the association with MCRD and IUGR is related to MCGs. Study design, size, duration Young adult female BALB/c mice were paired with males until vaginal plug formation was verified. Females were randomly assigned to two groups: control and phase-advance. Controls remained on a constant 12-hr light:12-hr dark cycle, whereas phase-advanced mice were subjected to 6-hr advances in the LD cycle every 5 days. Placentae (n = 1329) and fetuses were obtained from 144 mice at Zeitgeber time (ZT)0, ZT6, ZT12, and ZT18 days 12, 14, and 16 of pregnancy. Participants/materials, setting, methods The following analysis was performed: (i) open field test was used for locomotor activity evaluations to confirm MCRD, (ii) placenta/fetus weight ratio for evaluation of IUGR development, (iii) morphometric evaluation of placental compartments utilizing H&E staining (iv) gene expression analysis of MCGs utilizing qRT-PCR. One-way and Two-way ANOVA test followed by Holm-Sidak posthoc test was used for multiple comparisons. Values are expressed as mean ± standard error, and values below p < 0.05 were considered statistically significant. Main results and the role of chance Expression of MCGs (Bmal1, Clock, Npas2, Per1, Per2, Per3, Cry1, and Cry2) was rhythmic in the early and mature placenta development stages (days 12, 14, 16). Locomotor activity tests reveal that the total distance covered on the 16th day of pregnancy significantly decreased compared to the control group (p = 0.000158). The ratio of the time spent in the outer/inner quadrant, an anxiety indicator, significantly increased in the MCRD group on the 14th (p = 0.0351) and 16th days of pregnancy (p = 0.000329). While the number of fetuses was similar in both groups for all gestational days (p = 0.896), in the MCRD group, the fetus/placenta weight ratio decreased significantly on the 12th and 16th days of pregnancy (p < 0.001). Thus, IUGR developed due to MCRD. Histomorphometry analysis of the placental compartments revealed a significant reduction in the spongiotrophoblast layer’s size on all days of pregnancy and the labyrinth layer on day 16 (p < 0.05). Finally, the rhythmic expression MCGs were impaired in placentas obtained from MCRD groups on days 12th, 14th, 6th of pregnancy (p < 0.001). In conclusion, we found a robust relationship with the disturbed MCGs expression and occurrence of IUGR during a chrono-disrupted gestation. Limitations, reasons for caution Since this study was conducted in mice, care should be taken when translating the results to humans. Wider implications of the findings: Our results in mice are important for initiating basic science knowledge regarding the outcomes of maternal chrono-disruption. Moreover, research in the placenta of gestational chrono-disrupted mothers, such as shift-workers, are urgently needed to translate our findings into the clinic. Trial registration number TUBITAK–119S121 and Akdeniz University Research Projects Unit TYL–2018–3960

scholarly journals Clock Gene Expression in Adult Primate Suprachiasmatic Nuclei and Adrenal: Is the Adrenal a Peripheral Clock Responsive to Melatonin?

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1454-1461 ◽  
Author(s):  
F. J. Valenzuela ◽  
C. Torres-Farfan ◽  
H. G. Richter ◽  
N. Mendez ◽  
C. Campino ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Clock Gene ◽  
Clock Genes ◽  
Phase Relationship ◽  
Suprachiasmatic Nuclei ◽  
Rhythmic Expression ◽  
Peripheral Oscillators ◽  
Clock Gene Expression ◽  
Timing System ◽  
Circadian Timing System

The circadian production of glucocorticoids involves the concerted action of several factors that eventually allow an adequate adaptation to the environment. Circadian rhythms are controlled by the circadian timing system that comprises peripheral oscillators and a central rhythm generator located in the suprachiasmatic nucleus (SCN) of the hypothalamus, driven by the self-regulatory interaction of a set of proteins encoded by genes named clock genes. Here we describe the phase relationship between the SCN and adrenal gland for the expression of selected core clock transcripts (Per-2, Bmal-1) in the adult capuchin monkey, a New World, diurnal nonhuman primate. In the SCN we found a higher expression of Bmal-1 during the h of darkness (2000–0200 h) and Per-2 during daytime h (1400 h). The adrenal gland expressed clock genes in oscillatory fashion, with higher values for Bmal-1 during the day (1400–2000 h), whereas Per-2 was higher at nighttime (about 0200 h), resulting in a 9- to 12-h antiphase pattern. In the adrenal gland, the oscillation of clock genes was accompanied by rhythmic expression of a functional output, the steroidogenic enzyme 3β-hydroxysteroid dehydrogenase. Furthermore, we show that adrenal explants maintained oscillatory expression of Per-2 and Bmal-1 for at least 36 h in culture. The acrophase of both transcripts, but not its overall expression along the incubation, was blunted by 100 nm melatonin. Altogether, these results demonstrate oscillation of clock genes in the SCN and adrenal gland of a diurnal primate and support an oscillation of clock genes in the adrenal gland that may be modulated by the neurohormone melatonin.

scholarly journals The vascular clock: a new insight into endothelial cells and pericytes crosstalk

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
V Mastrullo ◽  
R S Matos ◽  
J H McVey ◽  
P Gupta ◽  
P Madeddu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Blood Vessels ◽  
Molecular Clock ◽  
Clock Genes ◽  
Public Institution ◽  
Perivascular Cells ◽  
Rhythmic Expression ◽  
The Impact

Abstract Background/Introduction Circadian rhythms, defined as biological oscillations with a period of circa 24h, regulate many physiological processes in the cardiovascular system, such as vascular function, vascular tone, blood pressure, heart rate and thrombus formation [1]. The vasculature responds to the main pacemaker located in the brain, but it also possesses its own clock. Indeed, a molecular clock has been identified in endothelial cells (EC) and smooth muscle cells (SMC). The disruption of the circadian clock profoundly affects cardiovascular functionality with adverse cardiovascular events such as myocardial infarction or stroke showing a 24h rhythmicity with a peak incidence in the early morning. Among several mechanisms affected by circadian dysregulation, angiogenesis plays a fundamental role in homeostasis and development of new blood vessels. EC and pericytes (PC) are the two main cell populations in the capillaries, and their physical and paracrine interaction drives and regulates the sprouting. However, the presence and the role of circadian rhythms in pericytes and whether the molecular clock affects the endothelial/pericyte interactions remain unexplored. Purpose The aim of this study is to identify a molecular clock in human vascular pericytes and elucidate the impact of the circadian clock on the formation of new blood vessels. Methods Human primary PC were synchronised and the rhythmicity of clock genes measured by luminescence, immunofluorescence, and qPCR. Synchronised PC were co-cultured with Bmal1::LUC human primary EC. The effect of PC synchronisation and circadian clock disruption by shRNA on EC clock genes and angiogenic potential were measured by luminescence and Matrigel assay, respectively. A macroporous polyurethane scaffold was developed for 3D co-cultures. Results PC presented rhythmic expression of the principal circadian genes with a circa 24h period but in our experimental setting, EC did not show circadian rhythmicity. Synchronised PC supported the rhythmic expression of the clock gene Bmal1 in EC in a contact co-culture system, suggesting a secondary form of EC molecular clock regulation. Non-contact co-cultures failed to synchronise EC. Furthermore, when the clock was disrupted in PC, their capacity to support EC's tube-forming capacity on Matrigel was impaired; clock disruption in EC did not affect angiogenesis, supporting the hypothesis that a disrupted clock in perivascular cells affects angiogenesis. In a 3D tissue engineering scaffold seeded with both EC and PC, the synchronisation of the clock led to the development of organised vascular-like structures around the scaffold's pores, as compared to the non-synchronised condition where cells appeared disorganised. Conclusion This study defines for the first time the existence of an endogenous molecular circadian clock in perivascular cells and suggests implications for circadian clock synchronisation in physiological and therapeutic angiogenesis. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Surrey Doctoral CollegeUniversity of Surrey Bioprocess and Biochemical Engineering (BioProChem) Group.

scholarly journals Maternal Obesity during Pregnancy Alters Daily Activity and Feeding Cycles, and Hypothalamic Clock Gene Expression in Adult Male Mouse Offspring

2019 ◽  
Vol 20 (21) ◽  
pp. 5408
Author(s):  
Jane K. Cleal ◽  
Kimberley D. Bruce ◽  
Jasmin L. Shearer ◽  
Hugh Thomas ◽  
Jack Plume ◽  
...  
Keyword(s):  
Gene Expression ◽  
Food Intake ◽  
Molecular Clock ◽  
Daily Activity ◽  
Maternal Obesity ◽  
Clock Genes ◽  
Expression Patterns ◽  
Altered Expression ◽  
Clock Gene Expression ◽  
Feeding Rhythms

An obesogenic diet adversely affects the endogenous mammalian circadian clock, altering daily activity and metabolism, and resulting in obesity. We investigated whether an obese pregnancy can alter the molecular clock in the offspring hypothalamus, resulting in changes to their activity and feeding rhythms. Female mice were fed a control (C, 7% kcal fat) or high fat diet (HF, 45% kcal fat) before mating and throughout pregnancy. Male offspring were fed the C or HF diet postweaning, resulting in four offspring groups: C/C, C/HF, HF/C, and HF/HF. Daily activity and food intake were monitored, and at 15 weeks of age were killed at six time-points over 24 h. The clock genes Clock, Bmal1, Per2, and Cry2 in the suprachiasmatic nucleus (SCN) and appetite genes Npy and Pomc in the arcuate nucleus (ARC) were measured. Daily activity and feeding cycles in the HF/C, C/HF, and HF/HF offspring were altered, with increased feeding bouts and activity during the day and increased food intake but reduced activity at night. Gene expression patterns and levels of Clock, Bmal1, Per2, and Cry2 in the SCN and Npy and Pomc in the ARC were altered in HF diet-exposed offspring. The altered expression of hypothalamic molecular clock components and appetite genes, together with changes in activity and feeding rhythms, could be contributing to offspring obesity.

scholarly journals Melatonin, Clock Genes, and Mammalian Reproduction: What Is the Link?

2021 ◽  
Vol 22 (24) ◽  
pp. 13240
Author(s):  
Amnon Brzezinski ◽  
Seema Rai ◽  
Adyasha Purohit ◽  
Seithikurippu R. Pandi-Perumal
Keyword(s):  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Molecular Clock ◽  
Reproductive Performance ◽  
Clock Genes ◽  
Current Knowledge ◽  
Reproductive Function ◽  
The Body ◽  
Molecular Clocks ◽  
Biological Regulation

Physiological processes and behaviors in many mammals are rhythmic. Recently there has been increasing interest in the role of circadian rhythmicity in the control of reproductive function. The circadian rhythm of the pineal hormone melatonin plays a role in synchronizing the reproductive responses of animals to environmental light conditions. There is some evidence that melatonin may have a role in the biological regulation of circadian rhythms and reproduction in humans. Moreover, circadian rhythms and clock genes appear to be involved in optimal reproductive performance. These rhythms are controlled by an endogenous molecular clock within the suprachiasmatic nucleus (SCN) in the hypothalamus, which is entrained by the light/dark cycle. The SCN synchronizes multiple subsidiary oscillators (clock genes) existing in various tissues throughout the body. The basis for maintaining the circadian rhythm is a molecular clock consisting of transcriptional/translational feedback loops. Circadian rhythms and clock genes appear to be involved in optimal reproductive performance. This mini review summarizes the current knowledge regarding the interrelationships between melatonin and the endogenous molecular clocks and their involvement in reproductive physiology (e.g., ovulation) and pathophysiology (e.g., polycystic ovarian syndrome).

scholarly journals Inhibition of IRS-1 Alters Retinal Circadian Clock

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Maaz Arif ◽  
Deepa Mathew ◽  
Ashay Bhatwadekar
Keyword(s):  
Gene Expression ◽  
Diabetic Retinopathy ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Insulin Signaling ◽  
Clock Genes ◽  
Regulatory Gene ◽  
Molecular Clocks ◽  
Temporal Dimension ◽  
Clock Gene Expression

Background and Hypothesis:  Life on Earth has adapted to a 24-hour cycle of light and darkness.  Circadian physiology coordinates temporal metabolism, hormone cycling, and sleep using clock genes. It is documented that dysregulation of clock gene expression is a key factor in the pathogenesis of diabetic retinopathy. Our goal was to explore the relationship between clock genes and the retina in diabetic milieu, and we hypothesized that disrupting downstream insulin signaling in a manner similar to diabetes in the retina would also affect the circadian clock.   Experimental Design or Project Methods: In this mouse study, we used a Per2::Luc fusion protein to perform  real-time bioluminescent recording of circadian rhythms. We used SecinH3 to inhibit Insulin Receptor Signaling (IRS-1). In isolated retinas, we modulated IRS-1 to mimic the diabetic condition of impaired insulin signaling; this allowed us to directly quantify circadian rhythms in the retina. Results: Our results show that IRS-1 inhibition by SecinH3 altered the gene expression of Per2, a clock regulatory gene, over the controls. There was an increase in the period and an apparent phase shift in the presence of 100uM SecinH3.   Conclusion and Potential Impact: Our findings can help us understand the role of insulin signaling on circadian rhythms of the retina and provide another temporal dimension to view diabetic retinopathy disease progression. Ultimately, further studies and a closer understanding of the roles of molecular clocks and insulin signaling may help to develop novel therapeutics for treating some of the harmful effects of diabetes.

scholarly journals Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
María Crespo ◽  
Barbara Gonzalez-Teran ◽  
Ivana Nikolic ◽  
Alfonso Mora ◽  
Cintia Folgueira ◽  
...  
Keyword(s):  
Molecular Clock ◽  
Immune Cells ◽  
Clock Gene ◽  
Clock Genes ◽  
Hepatic Metabolism ◽  
Neutrophil Infiltration ◽  
Fibroblast Growth Factor 21 ◽  
Clock Gene Expression ◽  
Jnk Activation ◽  
Fgf21 Expression

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.

scholarly journals CLOCK Genes and Circadian Rhythmicity in Alzheimer Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
J. Thome ◽  
A. N. Coogan ◽  
A. G. Woods ◽  
C. C. Darie ◽  
F. Häßler
Keyword(s):  
Alzheimer Disease ◽  
Clock Gene ◽  
Clock Genes ◽  
Sleep Problems ◽  
Internal Clock ◽  
Circadian Rhythmicity ◽  
Clock Gene Expression ◽  
Endogenous Clock ◽  
Exogenous Factors ◽  
The Impact

Disturbed circadian rhythms with sleep problems and disrupted diurnal activity are often seen in patients suffering from Alzheimer disease (AD). Both endogenous CLOCK genes and external Zeitgeber are responsible for the maintenance of circadian rhythmicity in humans. Therefore, modifications of the internal CLOCK system and its interactions with exogenous factors might constitute the neurobiological basis for clinically observed disruptions in rhythmicity, which often have grave consequences for the quality of life of patients and their caregivers. Presently, more and more data are emerging demonstrating how alterations of the CLOCK gene system might contribute to the pathophysiology of AD and other forms of dementia. At the same time, the impact of neuropsychiatric medication on CLOCK gene expression is under investigation.

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