297. Reproduction in the arrhythmic Bmal1 knockout mouse

2005 ◽  
Vol 17 (9) ◽  
pp. 126 ◽  
Author(s):  
M. J. Boden ◽  
D. J. Kennaway
Keyword(s):  
Knockout Mouse ◽  
Clock Genes ◽  
Reproductive Physiology ◽  
Circadian Rhythmicity ◽  
Wild Type ◽  
Epidemiological Evidence ◽  
Peripheral Tissues ◽  
Essentially Normal ◽  
The Impact ◽  
The Brain

There is strong epidemiological evidence indicating that disruption of the endogenous circadian rhythms can cause a range of health problems ranging from metabolic and cardiovascular disorders to reproductive failure. Circadian rhythmicity is generated by a suite of genes called ‘clock genes’ that are cyclically expressed in the brain and peripheral tissues. The CLOCK and BMAL1 transcription factors regulate the expression of many genes involved in cell growth, angiogenesis and development. The Bmal1 knockout mouse provides an interesting model to analyse the impact of arrhythmicity on reproductive physiology. Female Bmal1–/– mice show a delay in the onset of puberty (WT = 32.7 d, KO = 38.6 d, n = 8–16). Female Bmal1–/– mice reproductive tissues are significantly smaller than in WT mice (Ovaries –40%, Oviduct –25%, Uterus –60%, n = 10). Female Bmal1–/– mice have essentially normal estrus cycles (cycle length WT = 4.2 d, KO = 4.8 d, n = 8) and are able to ovulate and mate but are unable to establish viable pregnancies. They are as responsive to a standard superovulation protocol as their wild type littermates (ovulated oocytes WT = 23.8, KO=22.8, n = 7–10), suggesting the ovaries are developmentally competent. These results suggest disruption of circadian rhythmicity in the mouse affects fertility at multiple sites. Further investigation into the importance of rhythmicity, particularly post ovulation and post fertilisation is required.

scholarly journals 280.Reproductive consequences of circadian dysfunction: fertility in the Bmal1 null mouse

2004 ◽  
Vol 16 (9) ◽  
pp. 280 ◽  
Author(s):  
M. J. Boden ◽  
D. J. Kennaway
Keyword(s):  
Clock Genes ◽  
Reproductive Function ◽  
Blastocyst Stage ◽  
Null Mouse ◽  
Wild Type ◽  
Peripheral Tissues ◽  
Seminal Vesicle Weight ◽  
Natural Mating ◽  
Reproductive Consequences ◽  
The Brain

Circadian rhythms are generated by a suite of genes called clock genes that are expressed in the brain and also in many peripheral tissues. In the peripheral tissues, these genes assist in regulating the expression of many genes involved in cell growth, angiogenesis and development. Bmal1 is a critical gene involved in circadian rhythm generation. Here we report on the fertility and fecundity of Bmal1 knockout mice (Bmal1–/–). Male Bmal1–/– mice have impaired fertility compared to controls [(litters produced/number of animals) wild type (5/5), CBA controls (5/5), Bmal1–/– (1/15)]. Fifty percent of male Bmal1–/– mice had defective caudal sperm, showing sperm that was both non-motile and malformed. Seminal vesicle weight was significantly reduced in the Bmal1–/– mice (50% reduction) in males at both 4 and 5.5 months old. Female Bmal1–/– mice had irregular oestrus cycles and failed to maintain a pregnancy to term following natural mating [(litters produced/number of animals) wild type (5/5) CBA controls (5/5) Bmal1–/– (0/5)]. When embryos were flushed from the uterus 4 days after natural mating, there was a reduced number of released oocytes and a reduced development to blastocysts in the Bmal1–/– female mice. Following a standard PMSG/HCG super ovulation protocol, Bmal1–/– mice showed both a reduction in ovulation rate as well as a slowed progression of embryos to blastocyst stage (Table 1, see PDF file). These results suggest that disruption of a key clock gene has detrimental consequences on fertility in the mouse. Further, this reduction in fertility appears to be acting at multiple levels. Continued investigation into the importance of rhythm genes in reproductive function is required.

scholarly journals MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain

2018 ◽  
Vol 92 (8) ◽  
Author(s):  
E. Kip ◽  
J. Staal ◽  
L. Verstrepen ◽  
H. G. Tima ◽  
S. Terryn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Rabies Virus ◽  
T Cell Activation ◽  
Therapeutic Target ◽  
Cell Activation ◽  
Wild Type ◽  
The Impact ◽  
The Brain

ABSTRACTMALT1 is involved in the activation of immune responses, as well as in the proliferation and survival of certain cancer cells. MALT1 acts as a scaffold protein for NF-κB signaling and a cysteine protease that cleaves substrates, further promoting the expression of immunoregulatory genes. Deregulated MALT1 activity has been associated with autoimmunity and cancer, implicating MALT1 as a new therapeutic target. Although MALT1 deficiency has been shown to protect against experimental autoimmune encephalomyelitis, nothing is known about the impact of MALT1 on virus infection in the central nervous system. Here, we studied infection with an attenuated rabies virus, Evelyn-Rotnycki-Abelseth (ERA) virus, and observed increased susceptibility with ERA virus in MALT1−/−mice. Indeed, after intranasal infection with ERA virus, wild-type mice developed mild transient clinical signs with recovery at 35 days postinoculation (dpi). Interestingly, MALT1−/−mice developed severe disease requiring euthanasia at around 17 dpi. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1−/−mice at 10 dpi compared to MALT1+/+infected mice. At 17 dpi, however, the level of inflammatory cell activation was comparable to that observed in MALT1+/+mice. Moreover, MALT1−/−mice failed to produce virus-neutralizing antibodies. Similar results were obtained with specific inactivation of MALT1 in T cells. Finally, treatment of wild-type mice with mepazine, a MALT1 protease inhibitor, also led to mortality upon ERA virus infection. These data emphasize the importance of early inflammation and activation of T cells through MALT1 for controlling the virulence of an attenuated rabies virus in the brain.IMPORTANCERabies virus is a neurotropic virus which can infect any mammal. Annually, 59,000 people die from rabies. Effective therapy is lacking and hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protein involved in innate and adaptive immunity and is an interesting therapeutic target because MALT1-deregulated activity has been associated with autoimmunity and cancers. The role of MALT1 in viral infection is, however, largely unknown. Here, we study the impact of MALT1 on virus infection in the brain, using the attenuated ERA rabies virus in different models of MALT1-deficient mice. We reveal the importance of MALT1-mediated inflammation and T cell activation to control ERA virus, providing new insights in the biology of MALT1 and rabies virus infection.

scholarly journals Information theory and the neuropeptidergic regulation of seasonal reproduction in mammals and birds

2011 ◽  
Vol 278 (1717) ◽  
pp. 2477-2485 ◽  
Author(s):  
Tyler J. Stevenson ◽  
Gregory F. Ball
Keyword(s):  
Mammalian Species ◽  
Reproductive Physiology ◽  
Environmental Cues ◽  
Naturally Occurring ◽  
Contingency Model ◽  
Neural Integration ◽  
Gonadotrophin Releasing Hormone ◽  
Environmental Amelioration ◽  
The Impact ◽  
The Brain

Seasonal breeding in the temperate zone is a dramatic example of a naturally occurring change in physiology and behaviour. Cues that predict periods of environmental amelioration favourable for breeding must be processed by the brain so that the appropriate responses in reproductive physiology can be implemented. The neural integration of several environmental cues converges on discrete hypothalamic neurons in order to regulate reproductive physiology. Gonadotrophin-releasing hormone-1 (GnRH1) and Kisspeptin (Kiss1) neurons in avian and mammalian species, respectively, show marked variation in expression that is positively associated with breeding state. We applied the constancy/contingency model of predictability to investigate how GnRH1 and Kiss1 integrate different environmental cues to regulate reproduction. We show that variation in GnRH1 from a highly seasonal avian species exhibits a predictive change that is primarily based on contingency information. Opportunistic species have low measures of predictability and exhibit a greater contribution of constancy information that is sex-dependent. In hamsters, Kiss1 exhibited a predictive change in expression that was predominantly contingency information and is anatomically localized. The model applied here provides a framework for studies geared towards determining the impact of variation in climate patterns to reproductive success in vertebrate species.

scholarly journals Presence of a D2 receptor truncated protein in the brain of the D2 receptor functional knockout mouse, revisiting its molecular and neurochemical features

2019 ◽  
Author(s):  
Natalia Sánchez ◽  
Montserrat Olivares-Costa ◽  
Marcela P González ◽  
Angélica P Escobar ◽  
Rodrigo Meza ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Knockout Mouse ◽  
Transmembrane Domain ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Wild Type ◽  
Intracellular Loop ◽  
Protein Protein Interaction ◽  
Acute Injection ◽  
The Brain

AbstractNull mice for the dopamine D2 receptor (D2R) have been instrumental in understanding the function of this protein in the central nervous system. Several lines of D2R knockout mice have been generated, which share some characteristics but differ in others. The D2R functional knockout mouse, first described in 1997, is functionally null for D2R-mediated signaling but the Drd2 gene was interrupted at the most extreme distal end leaving open the question about whether transcript and protein are produced. We decided to determine if there are D2R transcripts, the characteristics of these transcripts and whether they are translated in the brain of D2R functional knockout mice. Sequence analysis of 3’ Rapid Amplification of cDNA Ends showed that D2R functional knockout mice express transcripts that lack only the exon eight. Immunofluorescence showed D2R-like protein in the brain of the knockout mice. As previously reported, D2R functional knockout mice are hypoactive and insensitive to the D2R agonist quinpirole (QNP). However, the heterozygous showed locomotor activity and response to QNP similar to the wild-type mice. Intriguingly, microdialysis experiments showed that heterozygous mice, such as knockouts, have half the normal levels of synaptic dopamine in the striatum. However, heterozygous mice responded similarly to wild-type mice to an acute injection of QNP, showing a 50% decrease in synaptic dopamine. In conclusion, D2R functional knockout mice express transcripts that lead to a truncated D2R protein that lacks from the sixth transmembrane domain to the C-terminal end but retains the third intracellular loop. We discuss the implications of this truncated D2R coexisting with the native D2R that may explain the unexpected outcomes observed in the heterozygous. Finally, we suggest that the D2R functional knockout mouse can be a useful model for studying protein-protein interaction and trafficking of D2R.

scholarly journals The Vascular Circadian Clock in Chronic Kidney Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1769
Author(s):  
Søren Egstrand ◽  
Maria L. Mace ◽  
Klaus Olgaard ◽  
Ewa Lewin
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Circadian Clock ◽  
Vascular Function ◽  
Clock Genes ◽  
Peripheral Tissues ◽  
Circadian Clock Genes ◽  
Vascular Physiology ◽  
Novel Concept ◽  
The Impact

Chronic kidney disease is associated with extremely high cardiovascular mortality. The circadian rhythms (CR) have an impact on vascular function. The disruption of CR causes serious health problems and contributes to the development of cardiovascular diseases. Uremia may affect the master pacemaker of CR in the hypothalamus. A molecular circadian clock is also expressed in peripheral tissues, including the vasculature, where it regulates the different aspects of both vascular physiology and pathophysiology. Here, we address the impact of CKD on the intrinsic circadian clock in the vasculature. The expression of the core circadian clock genes in the aorta is disrupted in CKD. We propose a novel concept of the disruption of the circadian clock system in the vasculature of importance for the pathology of the uremic vasculopathy.

scholarly journals Is FAM19A5 an adipokine? Peripheral FAM19A5 in wild-type, FAM19A5 knock-out, and LacZ knock-in mice

2020 ◽  
Author(s):  
Hoyun Kwak ◽  
Eun-Ho Cho ◽  
Eun Bee Cho ◽  
Yoo-Na Lee ◽  
Anu Shahapal ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Hek293 Cells ◽  
Extracellular Matrix Protein ◽  
Dependent Manner ◽  
Wild Type ◽  
Adipose Tissues ◽  
Peripheral Tissues ◽  
Knock Out ◽  
Protein Levels ◽  
The Brain

AbstractFAM19A5 (also called TAFA5) is a novel secretory protein that is primarily expressed in the brain. However, a recent study reported that FAM19A5 is an adipocyte-derived adipokine that regulates vascular smooth muscle function. Furthermore, genome-wide association study (GWAS) and RNA-seq analyses revealed that the FAM19A5 was associated with a variety of diseases and tumorigenesis in peripheral tissues. We investigated FAM19A5 transcript and protein levels in the peripheral tissues, including adipose tissues from wild-type, FAM19A5 knock-out, and LacZ knock-in mice. In general, total FAM19A5 transcript levels in the central and peripheral nervous systems were higher than levels in any of the peripheral tissues including adipose tissues. Brain tissues expressed similar levels of the FAM19A5 transcript isoforms 1 and 2, whereas expression in the peripheral tissues predominantly expressed isoform 2. In the peripheral tissues, but not the brain, FAM19A5 protein levels in adipose and reproductive tissues were below detectable limits for analysis by Western blot. Additionally, we found that FAM19A5 protein did not interact with the S1PR2 receptor for G-protein-mediated signal transduction, β-arrestin recruitment, and ligand-mediated internalization. Instead, FAM19A5 was internalized into HEK293 cells in an extracellular matrix protein-dependent manner. Taken together, the present study determined basal levels of FAM19A5 transcripts and proteins in peripheral tissues, which provides compelling evidence to further investigate the function of FAM19A5 in peripheral tissues under pathological conditions, including metabolic diseases and/or tumorigenesis.

scholarly journals microRNA-25 as a novel modulator of circadian Period2 gene oscillation

2020 ◽  
Vol 52 (9) ◽  
pp. 1614-1626
Author(s):  
Inah Park ◽  
Doyeon Kim ◽  
Jeongah Kim ◽  
Sangwon Jang ◽  
Mijung Choi ◽  
...  
Keyword(s):  
Posttranscriptional Regulation ◽  
Clock Genes ◽  
Brain Regions ◽  
Circadian Rhythmicity ◽  
Fine Tuning ◽  
Luciferase Reporter ◽  
Circadian Oscillation ◽  
Peripheral Tissues ◽  
Novel Mirna ◽  
Mirna 25

Abstract Circadian clock controls an organism’s biological rhythm and regulates its physiological processes in response to external time cues. Most living organisms have their own time-keeping mechanism that is maintained by transcriptional–translational autoregulatory feedback loops involving several core clock genes, such as Period. Recent studies have found the relevance between the modulation of circadian oscillation and posttranscriptional modifications by microRNAs (miRNAs). However, there are limited studies on candidate miRNAs that regulate circadian oscillation. Here, we characterize the functions of novel miRNA-25 regulating circadian Period2 (Per2) expression. Using several in silico algorithms, we identified novel miR-25-3p that, together with miR-24-3p, targets the Per2 gene. Luciferase reporter assays validated that miR-25-3p and miR-24-3p repressed Per2 expression and confirmed their predicted binding sites in the 3′-untranslated region (UTR) of Per2 mRNA. Real-time bioluminescence analyses using Per2::Luc mouse embryonic fibroblasts confirmed that PER2 protein oscillation patterns were responsive to miR-25-3p and miR-24-3. The overexpression of miR-25-3p or miR-24-3p resulted in the dampening and period shortening of the PER2::LUC oscillation, while inhibition of either miRNA increased the relative amplitude of the PER2::LUC oscillation. Notably, endogenous miR-25-3p expression in the suprachiasmatic nucleus (SCN) showed no circadian rhythmicity, but the expression levels differed in various brain regions and peripheral tissues. These results suggest that the posttranscriptional regulation of miR-25-3p and miR-24-3p may differ according to Per2 gene expression in different tissue regions. In summary, we found that novel miR-25-3p was involved in fine-tuning circadian rhythmicity by regulating Per2 oscillation at the posttranscriptional level and that it functioned synergistically with miR-24-3p to affect Per2 oscillation.

scholarly journals Off the Clock: From Circadian Disruption to Metabolic Disease

2019 ◽  
Vol 20 (7) ◽  
pp. 1597 ◽  
Author(s):  
Eleonore Maury
Keyword(s):  
Metabolic Disease ◽  
Metabolic Disorders ◽  
Jet Lag ◽  
High Fat ◽  
Peripheral Tissues ◽  
Temporal Regulation ◽  
The Impact ◽  
Fat Feeding ◽  
The Brain ◽  
Daily Changes

Circadian timekeeping allows appropriate temporal regulation of an organism’s internal metabolism to anticipate and respond to recurrent daily changes in the environment. Evidence from animal genetic models and from humans under circadian misalignment (such as shift work or jet lag) shows that disruption of circadian rhythms contributes to the development of obesity and metabolic disease. Inappropriate timing of food intake and high-fat feeding also lead to disruptions of the temporal coordination of metabolism and physiology and subsequently promote its pathogenesis. This review illustrates the impact of genetically or environmentally induced molecular clock disruption (at the level of the brain and peripheral tissues) and the interplay between the circadian system and metabolic processes. Here, we discuss some mechanisms responsible for diet-induced circadian desynchrony and consider the impact of nutritional cues in inter-organ communication, with a particular focus on the communication between peripheral organs and brain. Finally, we discuss the relay of environmental information by signal-dependent transcription factors to adjust the timing of gene oscillations. Collectively, a better knowledge of the mechanisms by which the circadian clock function can be compromised will lead to novel preventive and therapeutic strategies for obesity and other metabolic disorders arising from circadian desynchrony.

scholarly journals Metabolomic and lipidomic changes triggered by lipopolysaccharide-induced systemic inflammation in transgenic APdE9 mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elena Puris ◽  
Štěpán Kouřil ◽  
Lukáš Najdekr ◽  
Sanna Loppi ◽  
Paula Korhonen ◽  
...  
Keyword(s):  
Disease Progression ◽  
Brain Tissue ◽  
Systemic Inflammation ◽  
Metabolic Pathways ◽  
Wild Type ◽  
The Impact ◽  
The Brain ◽  
Lps Treatment

AbstractPeripheral infections followed by systemic inflammation may contribute to the onset of Alzheimer`s disease (AD) and accelerate the disease progression later in life. Yet, the impact of systemic inflammation on the plasma and brain tissue metabolome and lipidome in AD has not been investigated. In this study, targeted metabolomic and untargeted lipidomic profiling experiments were performed on the plasma, cortices, and hippocampi of wild-type (WT) mice and transgenic APdE9 mice after chronic lipopolysaccharide (LPS) treatment, as well as saline-treated APdE9 mice. The lipidome and the metabolome of these mice were compared to saline-treated WT animals. In the brain tissue of all three models, the lipidome was more influenced than the metabolome. The LPS-treated APdE9 mice had the highest number of changes in brain metabolic pathways with significant alterations in levels of lysine, myo-inositol, spermine, phosphocreatine, acylcarnitines and diacylglycerols, which were not observed in the saline-treated APdE9 mice. In the WT mice, the effect of the LPS administration on metabolome and lipidome was negligible. The study provided exciting information about the biochemical perturbations due to LPS-induced inflammation in the transgenic AD model, which can significantly enhance our understanding of the role of systemic inflammation in AD pathogenesis.

scholarly journals The impact of the gut microbiome on memory and sleep in Drosophila

2020 ◽  
pp. jeb.233619
Author(s):  
Valeria Silva ◽  
Angelina Palacios-Muñoz ◽  
Zeynep Okray ◽  
Karen L. Adair ◽  
Scott Waddell ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Gut Microbiome ◽  
Memory Performance ◽  
Circadian Rhythmicity ◽  
Appetitive Conditioning ◽  
Wild Type ◽  
Behavioral Traits ◽  
Moderate Reduction ◽  
The Impact ◽  
Type Strains

The gut microbiome has been proposed to influence diverse behavioral traits of animals, although the experimental evidence is limited and often contradictory. Here, we make use of the tractability of Drosophila melanogaster for both behavioral analyses and microbiome studies to test how elimination of microorganisms affects a number of behavioral traits. Relative to conventional flies (i.e., with unaltered microbiome), microbiologically-sterile (axenic) flies displayed a moderate reduction in memory performance in olfactory appetitive conditioning and courtship assays. The microbiological status of the flies had small or no effect on anxiety-like behavior (centrophobism) or circadian rhythmicity of locomotor activity, but axenic flies tended to sleep for longer and displayed reduced sleep rebound after sleep deprivation. The latter effects were robust for most tests conducted on both wildtype Canton S and w1118 strains, as well for tests using an isogenized panel of flies with mutations in the period gene, which causes altered circadian rhythmicity. Interestingly, the effect of absence of microbiota on a few behavioral features, most notably instantaneous locomotor activity speed, varied among wild-type strains. Taken together, our findings demonstrate that the microbiome can have subtle but significant effects on specific aspects of Drosophila behavior, some of which are dependent on genetic background.

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