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.

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 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.

Transthyretin is not essential for thyroxine to reach the brain and other tissues in transthyretin-null mice

1997 ◽  
Vol 272 (3) ◽  
pp. E485-E493 ◽  
Author(s):  
J. A. Palha ◽  
M. T. Hays ◽  
G. Morreale de Escobar ◽  
V. Episkopou ◽  
M. E. Gottesman ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Null Mouse ◽  
Tissue Uptake ◽  
Wild Type ◽  
Transfer Rates ◽  
Physiological Conditions ◽  
Liver And Kidney ◽  
The Brain ◽  
Brain Barriers

As part of a study on tissue uptake of thyroxine (T4) in a transthyretin (TTR)-null mouse strain, kinetic parameters of thyroxine metabolism in wild-type mice under normal physiological conditions are presented. Kinetic analysis of injected [(125)I]T4 showed that TTR-null mutants have markedly increased [(125)I]T4 transfer rate constants from plasma to the fast-exchange compartments of liver and kidney and from fast to slow kidney compartments. Transfer rates from plasma to brain, testes, and fat were little affected. The T4 tissue content in the mutants was greatly reduced in brain but relatively normal in liver and kidney. No major changes were observed in brain 3,3',5-triiodothyronine concentrations, suggesting that availability of this hormone is not markedly altered in the mutant mice. The low T4 brain content probably reflects the absence of T4-TTR complexes in the mutant choroid plexus and cerebrospinal fluid. This study indicates that TTR is not essential for T4 tissue uptake or for T4 to reach the brain across the choroid plexus-cerebrospinal fluid and/or blood-brain barriers.

Circadian clock genes in reproductive tissues and the developing conceptus

2009 ◽  
Vol 21 (1) ◽  
pp. 1 ◽  
Author(s):  
Hamid Dolatshad ◽  
Fred C. Davis ◽  
Martin H. Johnson
Keyword(s):  
Circadian Clock ◽  
Clock Genes ◽  
Reproductive Function ◽  
Current Data ◽  
Published Data ◽  
Peripheral Tissues ◽  
Genetic Manipulations ◽  
Reproductive Tissues ◽  
Circadian Clock Genes ◽  
Physiological And Biochemical

The circadian (near 24-h) clock is involved in the temporal organisation of physiological and biochemical activities of many organisms, including humans. The clock functions through the rhythmic transcription and translation of several genes, forming an oscillatory feedback loop. Genetic analysis has shown that the circadian clock exists in both a central circadian pacemaker (i.e. the suprachiasmatic nucleus of the hypothalamus), as well as in most peripheral tissues. In particular, the circadian clockwork genes are expressed in all female and male reproductive tissues studied so far, as well as in the conceptus itself. The current data clearly show a robust rhythm in female reproductive tissues, but whether rhythmicity also exists in male reproductive tissues remains uncertain. Although the conceptus also expresses most of the canonical circadian genes, the rhythmicity of their expression is still under investigation. Published data indicate that environmental and genetic manipulations influence reproductive function and fecundity, suggesting an important role for the circadian clock in reproduction, and possibly early development.

Regulators and Integration of Peripheral Signals

2021 ◽  
Author(s):  
Michelle T. Foster
Keyword(s):  
Adipose Tissue ◽  
Reproductive Function ◽  
Energy Regulation ◽  
Energy Status ◽  
Peripheral Tissues ◽  
Reproductive Axis ◽  
Reproductive Events ◽  
Ovarian Cyclicity ◽  
Reproductive Processes ◽  
The Brain

In mammals, reproductive function is closely regulated by energy availability. It is influenced by both extremes of nutrition, too few calories (undernutrition) and an excessive amount of calories (obesity). Atypical decreases or increases in weight can have adverse effects on the reproductive axis. This includes suppression of reproductive function, decreases in ovarian cyclicity, reduction in fertility, anovulation, and dysregulation of spermatogenesis. The balance between energy regulation and reproduction is supervised by a complex system comprised of the brain and peripheral tissues. The brain senses and integrates various systemic and central signals that are indicative of changes in body physiology and energy status. This occurs via numerous factors, including metabolic hormones and nutrients. Adipokines, endocrine factors primarily secreted by white adipose tissue, and adipose tissue related cytokines (adipocytokines) contribute to the regulation of maturity, fertility, and reproduction. Indeed, some adipokines play a fundamental role in reproductive disorders. The brain, predominantly the hypothalamus, is responsible for linking adipose-derived signals to pathways controlling reproductive processes. Gonadotropin-releasing hormone (GnRH) cells in the hypothalamus are fundamental in relaying adipose-derived signals to the pituitary–gonadal axis, which consequently controls reproductive processes. Leptin, adiponectin, apelin, chermin, resistin, and visfatin are adipokines that regulate reproductive events via the brain.

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

scholarly journals Modeling temperature- and Cav3 subtype-dependent alterations in T-type calcium channel mediated burst firing

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Fernando R. Fernandez ◽  
Mircea C. Iftinca ◽  
Gerald W. Zamponi ◽  
Ray W. Turner
Keyword(s):  
Calcium Channel ◽  
Neuronal Excitability ◽  
Neuronal Firing ◽  
Mammalian Brain ◽  
Peripheral Tissues ◽  
Window Current ◽  
Modeling Data ◽  
The Brain ◽  
Firing Neuron ◽  
Cav3 Channel

AbstractT-type calcium channels are important regulators of neuronal excitability. The mammalian brain expresses three T-type channel isoforms (Cav3.1, Cav3.2 and Cav3.3) with distinct biophysical properties that are critically regulated by temperature. Here, we test the effects of how temperature affects spike output in a reduced firing neuron model expressing specific Cav3 channel isoforms. The modeling data revealed only a minimal effect on baseline spontaneous firing near rest, but a dramatic increase in rebound burst discharge frequency for Cav3.1 compared to Cav3.2 or Cav3.3 due to differences in window current or activation/recovery time constants. The reduced response by Cav3.2 could optimize its activity where it is expressed in peripheral tissues more subject to temperature variations than Cav3.1 or Cav3.3 channels expressed prominently in the brain. These tests thus reveal that aspects of neuronal firing behavior are critically dependent on both temperature and T-type calcium channel subtype.

scholarly journals Breeder Diet Strategies for Generating Ttpa-Null and Wild-Type Mice with Low Vitamin E Status to Assess Neurological Outcomes

2020 ◽  
Vol 4 (11) ◽  
Author(s):  
Katherine M Ranard ◽  
Matthew J Kuchan ◽  
John W Erdman
Keyword(s):  
Animal Model ◽  
Vitamin E ◽  
Mouse Model ◽  
Wild Type ◽  
Future Studies ◽  
Neurological Outcomes ◽  
Transfer Protein ◽  
And Function ◽  
The Brain ◽  
Vitamin E Status

ABSTRACT Studying vitamin E [α-tocopherol (α-T)] metabolism and function in the brain and other tissues requires an animal model with low α-T status, such as the transgenic α-T transfer protein (Ttpa)–null (Ttpa−/−) mouse model. Ttpa+/− dams can be used to produce Ttpa−/− and Ttpa+/+mice for these studies. However, the α-T content in Ttpa+/− dams’ diet requires optimization; diets must provide sufficient α-T for reproduction, while minimizing the transfer of α-T to the offspring destined for future studies that require low baseline α-T status. The goal of this work was to assess the effectiveness and feasibility of 2 breeding diet strategies on reproduction outcomes and offspring brain α-T concentrations. These findings will help standardize the breeding methodology used to generate the Ttpa−/− mice for neurological studies.

scholarly journals BDNF haploinsufficiency induces behavioral endophenotypes of schizophrenia in male mice that are rescued by enriched environment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mahmoud Harb ◽  
Justina Jagusch ◽  
Archana Durairaja ◽  
Thomas Endres ◽  
Volkmar Leßmann ◽  
...  
Keyword(s):  
Prepulse Inhibition ◽  
Sensorimotor Gating ◽  
Enriched Environment ◽  
Fear Learning ◽  
Set Shifting ◽  
Wild Type ◽  
Mature Adult ◽  
Attentional Set ◽  
Attentional Set Shifting ◽  
The Brain

AbstractBrain-derived neurotrophic factor (BDNF) is implicated in a number of processes that are crucial for healthy functioning of the brain. Schizophrenia is associated with low BDNF levels in the brain and blood, however, not much is known about BDNF’s role in the different symptoms of schizophrenia. Here, we used BDNF-haploinsufficient (BDNF+/−) mice to investigate the role of BDNF in different mouse behavioral endophenotypes of schizophrenia. Furthermore, we assessed if an enriched environment can prevent the observed changes. In this study, male mature adult wild-type and BDNF+/− mice were tested in mouse paradigms for cognitive flexibility (attentional set shifting), sensorimotor gating (prepulse inhibition), and associative emotional learning (safety and fear conditioning). Before these tests, half of the mice had a 2-month exposure to an enriched environment, including running wheels. After the tests, BDNF brain levels were quantified. BDNF+/− mice had general deficits in the attentional set-shifting task, increased startle magnitudes, and prepulse inhibition deficits. Contextual fear learning was not affected but safety learning was absent. Enriched environment housing completely prevented the observed behavioral deficits in BDNF+/− mice. Notably, the behavioral performance of the mice was negatively correlated with BDNF protein levels. These novel findings strongly suggest that decreased BDNF levels are associated with several behavioral endophenotypes of schizophrenia. Furthermore, an enriched environment increases BDNF protein to wild-type levels and is thereby able to rescue these behavioral endophenotypes.

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.

Sign in / Sign up

Export Citation Format

Share Document