The mortality of MOP3 deficient mice with a systemic functional failure

Sun, Yimin; Yang, Zhihui; Niu, Ze‐Qing; Wang, Wenle; Peng, Jianxiao; Li, Qinghuan; Mark, Y. J.; Zhao, Yong

doi:10.1007/s11373-006-9108-4

Cited by 38 publications

(27 citation statements)

References 11 publications

(11 reference statements)

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“…The Bmal1 null pups weighed significantly less than wild-type mice at weaning and failed to catch up. This finding differs slightly from previous reports (Bunger et al 2005, Sun et al 2006, where decreased BW only became evident around 20 weeks of age, secondary to progressive arthropathy interfering with normal feeding.…”

Section: Discussioncontrasting

confidence: 99%

“…Therefore, as discussed above, the absence of Bmal1 gene expression may be expected to have a profound effect on reproduction. Interestingly, Bmal1 null mice have been described as 'viable and fertile' (Cowden & Simon 2002), although subsequent studies identified a spectrum of physiological changes (Kondratov et al 2006, McDearmon et al 2006, Sun et al 2006. In this report, we describe comprehensive studies on the reproductive biology of female Bmal1 null mice.…”

Section: Introductionmentioning

confidence: 89%

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Reproductive biology of female Bmal1 null mice

Boden¹,

Varcoe²,

Voultsios³

et al. 2010

Reproduction

119

125

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The light/dark cycle and suprachiasmatic nucleus rhythmicity are known to have important influences on reproductive function of rodents. We studied reproductive function in female heterozygous and homozygous brain and muscle ARNT-like protein 1 (Bmal1, also known as Arntl ) null mice, which lack central and peripheral cellular rhythms. Heterozygous Bmal1 mice developed normally and were fertile, with apparent normal pregnancy progression and litter size, although postnatal mortality up to weaning was high (1.1-1.3/litter). The genotype distribution was skewed with both heterozygous and null genotypes underrepresented (1.0:1.7:0.7; P!0.05), suggesting loss of a single Bmal1 allele may impact on postnatal survival. Homozygous Bmal1 null mice were 30% lighter at weaning, and while they grew at a similar rate to the wild-type mice, they never achieved a comparable body weight. They had delayed vaginal opening (4 days), disrupted estrus cyclicity, and reduced ovarian weight (30%). Bmal1 null mice had a 40% reduction in ductal length and a 43% reduction in ductal branches in the mammary gland. Surprisingly, the Bmal1 mice ovulated, but progesterone synthesis was reduced in conjunction with altered corpora lutea formation. Pregnancy failed prior to implantation presumably due to poor embryo development. While Bmal1 null ovaries responded to pregnant mare serum gonadotropin/human chorionic gonadotropin stimulation, ovulation rate was reduced, and the fertilized oocytes progressed poorly to blastocysts and failed to implant. The loss of Bmal1 gene expression resulted in a loss of rhythmicity of many genes in the ovary and downregulation of Star. In conclusion, it is clear that the profound infertility of Bmal1 null mice is multifactorial.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Reproductive biology of female Bmal1 null mice

Boden¹,

Varcoe²,

Voultsios³

et al. 2010

Reproduction

119

125

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“…The presence of functional CRY products appears essential for tuning the ultradian GH pulsatility required for the male-specific liver activity. Similarly, previous studies reported that the circadian clock gene Bmal1 is also necessary to maintain male-female differences in body growth (33) or that liver expression of Elovl3 follows a female-like profile in male homozygous Clock/Clock mutants (19). Moreover, male rats with lesioned SCN exhibit a feminized steroid metabolism (37), as we observed for Cry Ϫ/Ϫ mice.…”

Section: Circadian Timekeeping As a Regulator Of Ultradian Ghsupporting

confidence: 85%

“…Firstly, previous studies reported that clock-deficient Bmal1 Ϫ/Ϫ or Cry Ϫ/Ϫ mice are significantly smaller than control animals (31)(32)(33). This prompted us to systematically compare the postnatal growth of Cry Ϫ/Ϫ males and females.…”

Section: Dimorphic Traits Dependent On Ultradian Gh Pulsatility Are Fmentioning

confidence: 99%

The Circadian Clock Components CRY1 and CRY2 Are Necessary to Sustain Sex Dimorphism in Mouse Liver Metabolism

Bur

Cohen-Solal

Carmignac

et al. 2009

Journal of Biological Chemistry

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In mammals, males and females exhibit anatomical, hormonal, and metabolic differences. A major example of such sex dimorphism in mouse involves hepatic drug metabolism, which is also a noticeable target of circadian timekeeping. However, whether the circadian clock itself contributes to sex-biased metabolism has remained unknown, although several daily output parameters differ between sexes in a number of species, including humans. Here we show that dimorphic liver metabolism is altered when the circadian regulators Cryptochromes, Cry1 and Cry2, are inactivated. Indeed, double mutant Cry1 Cry2؊/؊ male mice that lack a functional circadian clock express a number of sex-specific liver products, including several cytochrome P450 enzymes, at levels close to those measured in females. In addition, body growth of Cry-deficient mice is impaired, also in a sex-biased manner, and this phenotype goes along with an altered pattern of circulating growth hormone (GH) in mutant males, specifically. It is noteworthy that hormonal injections able to mimic male GH pulses reversed the feminized gene expression profile in the liver of Cry1 ؊/؊ Cry2 ؊/؊ males. Altogether, our observations suggest that the 24-h clock paces the dimorphic ultradian pulsatility of GH that is responsible for sex-dependent liver activity. We thus conclude that circadian timing, sex dimorphism, and liver metabolism are finely interconnected.Phenotypic differences between males and females of a given species exist from invertebrates to humans and cover various features including disease susceptibility and life span, for example. Although the anatomical and hormonal differences between sexes are well described, few genetic determinants are known to account for sexual dimorphism in mammals. Recent genome-wide studies on various mouse tissues showed that major differences in gene expression between males and females involve drug metabolism (1, 2), and among somatic organs, the sex-biased transcriptional activity is particularly high in the liver (3-5). These observations may provide insight into why many drugs exhibit a faster clearance in women as compared with men (6) but also underscore the importance of considering sex issues in studies on liver metabolism.Interestingly, liver activity also fluctuates along the light-dark cycle and is a noticeable target of circadian timekeeping (7-9). Both systemic cues and a circadian clock within hepatocytes are involved in daily oscillations of liver metabolism (10, 11). However, because most of these studies were focused on males exclusively, the possible interaction between circadian oscillators and sex dimorphism of hepatic activity is not documented.This prompted us to investigate whether circadian cogwheels could also be involved in the sexual dimorphism observed at the hepatic level. Indeed, several daily output parameters differ between sexes in a number of species, including humans (12)(13)(14), which may reflect the ability of the suprachiasmatic nuclei (SCN), 3 where the central pacemaker resides, to sense s...

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“…The functional circadian clock systems are detected in major immune cells, including macrophages (63), B cells (64,65), and natural killer cells (66 -68). It has been reported that circadian clock disruption via the shifted light/dark cycle or genetic deletion of clock genes impairs innate immunity and response to LPS treatment in mice (22,61,63).…”

Section: Serum Shock Enhances the Cry1 Protein Deubiquitination Bymentioning

confidence: 99%

USP2a Protein Deubiquitinates and Stabilizes the Circadian Protein CRY1 in Response to Inflammatory Signals

Tong

Buelow

Guha

et al. 2012

Journal of Biological Chemistry

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Background: Ubiquitination-dependent proteasome degrades CRY1. However, the deubiquitination enzyme for CRY1 is unknown. Results: USP2a deubiquitinates and stabilizes CRY1 in vitro and in vivo. TNF-␣ stabilizes CRY1 via USP2a. Conclusion: USP2a functions to stabilize CRY1 during a circadian cycle and in response to TNF-␣ treatment. Significance: USP2a-dependent stabilization of CRY1 may mediate disruption of the clock function during inflammation.

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The mortality of MOP3 deficient mice with a systemic functional failure

Cited by 38 publications

References 11 publications

Reproductive biology of female Bmal1 null mice

Reproductive biology of female Bmal1 null mice

The Circadian Clock Components CRY1 and CRY2 Are Necessary to Sustain Sex Dimorphism in Mouse Liver Metabolism

USP2a Protein Deubiquitinates and Stabilizes the Circadian Protein CRY1 in Response to Inflammatory Signals

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