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The metabolic syndrome (MetS) is a complex constellation of metabolic abnormalities including obesity, abnormal glucose metabolism, dyslipidemia, and elevated blood pressure that together substantially increase risk for cardiovasc...
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The metabolic syndrome (MetS) is a complex constellation of metabolic abnormalities including obesity, abnormal glucose metabolism, dyslipidemia, and elevated blood pressure that together substantially increase risk for cardiovascular disease and Type 2 diabetes. Both genetic and environmental factors contribute to the development of MetS, but this process is still far from understood. Human studies have revealed only part of the underlying basis. Studies in mice offer many strengths that can complement human studies to help elucidate the etiology and pathophysiology of MetS. Here we review the ways mice can contribute to MetS research. In particular, we focus on the information that can be obtained from studies of the inbred strains, with specific focus on the phenotypes of the wild-derived inbred strains. These are newly derived inbred strains that were created from wild-caught mice. They contain substantial genetic variation that is not present in the classical inbred strains, have phenotypes of relevance for MetS, and various mouse strain resources have been created to facilitate the mining of this new genetic variation. Thus studies using wild-derived inbred strains hold great promise for increasing our understanding of MetS.
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Two inbred strains of the Mongolian gerbil with different phenotypes in seizure behaviour and coat color were newly established. LSAG/Nu has low seizure susceptibility and albino phenotypes, whereas SPBG/Nu has seizure-prone and b...
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Two inbred strains of the Mongolian gerbil with different phenotypes in seizure behaviour and coat color were newly established. LSAG/Nu has low seizure susceptibility and albino phenotypes, whereas SPBG/Nu has seizure-prone and black coat color phenotypes. LSAG was compared with SPBG as to seizure incidence and grade. Mean ages at seizure onset of LSAG and SPBG were 6 and 3 months, respectively. Seizure incidences in over 9 months old LSAG and SPBG gerbils were 37.3% (66/177) and 95.2% (118/124), respectively. LSAG has a significantly lower incidence (p<0.001) and grade (p<0.001) of seizures than SPBG. Only a few seizing LSAG gerbils exhibited myoclonus to tonic-clonic seizure progression. These results suggest that LSAG has some mechanisms which delay the onset of seizures and prevent them from becoming serious. Both strains of gerbils can be expected to be useful animal models for the study of human idiopathic generalized epilepsy.
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Our routine health-surveillance program is based on use of the Swiss Webster mouse, with sentinels submitted for testing every 7 weeks. Athymic nude (nu(+)/nu(+)) mice are used as an adjunct method to detect pinworm infections. Th...
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Our routine health-surveillance program is based on use of the Swiss Webster mouse, with sentinels submitted for testing every 7 weeks. Athymic nude (nu(+)/nu(+)) mice are used as an adjunct method to detect pinworm infections. The premise for the use of the nude mouse was based on research that revealed the thymus as necessary to confer resistance to pinworm infections. In light of this finding, it was inferred that an athymic mouse would be more susceptible to pinworm infections than a euthymic mouse, and hence a better sentinel animal for pinworm detection. To test the validity of this assumption, the Syphacia obvelata detection ability of the athymic nude mouse was compared to that of the Swiss Webster. Our results indicate no significant temporal difference in the detection ability of the two genotypes of mice. A clearance study for the parasite was also performed, in which the majority of Swiss Webster mice cleared the infection whereas athymic nude mice did not. In light of our results, we conclude that use of the athymic nude mouse for Syphacia obvelata detection offered no significant advantage over the euthymic Swiss Webster mouse for our program.
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High-throughput analyses have shown that aquaporins (AQPs) belong to a cluster of genes that are differentially expressed during kidney organogenesis. However, the spatiotemporal expression patterns of the AQP gene family during t...
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High-throughput analyses have shown that aquaporins (AQPs) belong to a cluster of genes that are differentially expressed during kidney organogenesis. However, the spatiotemporal expression patterns of the AQP gene family during tubular maturation and the potential influence of genetic variation on these patterns and on water handling remain unknown. We investigated the expression patterns of all AQP isoforms in fetal (E13.5 to E18.5), postnatal (P1 to P28), and adult (9 weeks) kidneys of inbred (C57BL/6J) and outbred (CD-1) mice. Using quantitative polymerase chain reaction (PCR), we evidenced two mRNA patterns during tubular maturation in C57 mice. The AQPs 1-7-11 showed an early (from E14.5) and progressive increase to adult levels, similar to the mRNA pattern observed for proximal tubule markers (Megalin, NaPi-IIa, OAT1) and reflecting the continuous increase in renal cortical structures during development. By contrast, AQPs 2-3-4 showed a later (E15.5) and more abrupt increase, with transient postnatal overexpression. Most AQP genes were expressed earlier and/or stronger in maturing CD-1 kidneys. Furthermore, adult CD-1 kidneys expressed more AQP2 in the collecting ducts, which was reflected by a significant delay in excreting a water load. The expression patterns of proximal vs. distal AQPs and the earlier expression in the CD-1 strain were confirmed by immunoblotting and immunostaining. These data (1) substantiate the clustering of important genes during tubular maturation and (2) demonstrate that genetic variability influences the regulation of the AQP gene family during tubular maturation and water handling by the mature kidney. Keywords Water handling - Inbred strain - Outbred strain - Mouse kidney
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In 230 mice from 12 inbred strains (A.CA/W, AKR/W, BALB/cW, BN/aW, CBA/W, CBA-T6/W, C3HAV, C57BL/6W, C57BL/10W, DBA2/W, 129Sl/SvW, HLB219/J) the following parameters were measured: the total number of white (WBC) and red (RBC) blo...
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In 230 mice from 12 inbred strains (A.CA/W, AKR/W, BALB/cW, BN/aW, CBA/W, CBA-T6/W, C3HAV, C57BL/6W, C57BL/10W, DBA2/W, 129Sl/SvW, HLB219/J) the following parameters were measured: the total number of white (WBC) and red (RBC) blood cells, haemoglobinconcentration (HGB), haematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC) and platelets (PLT) number. Highly significant interstrain differences were shown within RBC, HGB, HCT, MCV and PLT.
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The precise locations of attachment points of muscle to bone-the origin and insertion sites-are crucial anatomical and functional characteristics that influence locomotor performance. Mechanisms that control the development of the...
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The precise locations of attachment points of muscle to bone-the origin and insertion sites-are crucial anatomical and functional characteristics that influence locomotor performance. Mechanisms that control the development of these interactions between muscle, tendon, and bone are currently not well understood. In a subset of BXD recombinant inbred (RTj strains derived from the C57BL/6J and DBA/2J strains, we observed a soleus femoral attachment anomaly (SFAA) that was rare in both parental strains (Lionikas, Glover et al. 2006). The aim of the present study was to assess suitability of SFAA as a model to study the genetic mechanisms underlying variation in musculoskeletal anatomy. We scored the incidence of SFAA in 55 BXD strains (n = 9 to 136, median = 26, phenotyped animals per strain, for a total number of 2367). Seven strains (BXD1, 12, 38, 43, 48, 54, and 56) exhibited a high incidence of unilateral SFAA (47-89%), whereas 23 strains scored 0%. Exploration of the mechanisms underlying SFAA in 2 high incidence strains, BXD1 and BXD38, indicated that SFAA-relevant genes are to be found in both C57BL/6J and DBA/2J regions of the BXD1 genome. However, not all alleles relevant for the expression of the phenotype were shared between the 2 high-incidence BXD strains. In conclusion, the anatomical origin of the soleus muscle in mouse is controlled by a polygenic system. A panel of BXD RI strains is a useful tool in exploring the genetic mechanisms underlying SFAA and improving our understanding of musculoskeletal development.
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Many aspects of mouse behavior have been studied by using only a relatively small sample of available laboratory strains. These laboratory mice were derived from the so-called "fancy mouse" and in most cases underwent extensive do...
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Many aspects of mouse behavior have been studied by using only a relatively small sample of available laboratory strains. These laboratory mice were derived from the so-called "fancy mouse" and in most cases underwent extensive domestication before inbreeding. Thus, the behavioral repertoire of the laboratory mouse may be very different from that exhibited by stocks that have not been deliberately domesticated. Another inherent problem in analyzing mouse behavior is that genetic diversity is limited among currently available strains. In this respect, the use of strains that are derived from a variety of wild mice should provide a means to identifying novel behavioral phenotypes. We have investigated several behavioral phenotypes, using females of a number of mouse strains derived from wild mice of different subspecies, BFM/2, NJL, BLG2, HMI, CAST/Ei, KJR, SWN and MSM; a strain derived from fancy mice, JF1; and two laboratory strains, C57BL/6 and DBA/1. In this report, tests for locomotor activity, light-dark transitions, passive and active avoidance, and nociception were conducted. The results show great diversity of behavioral patterns between strains in contrast to less within-strain variability. We also found that two strains, KJR and SWN, both have good learning ability, whereas BLG2 mice exhibit impairment in both passive and active avoidance learning.
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Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, α-aminoadipic acidemia and branched-chain ketoacid dehydrogenase deficiency are ...
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Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, α-aminoadipic acidemia and branched-chain ketoacid dehydrogenase deficiency are known in C57BL/6J mice. Using RNA sequencing, we now reveal the causal variants in Dhtkdl and Bckdhb, and the molecular mechanism underlying these metabolic defects. C57BL/6J mice have decreased Dhtkdl mRNA expression due to a solitary long terminal repeat (LTR) in intron 4 of Dhtkd1. This LTR harbors an alternate splice donor site leading to a partial splicing defect and as a consequence decreased total and functional Dhtkdl mRNA, decreased DHTKD1 protein and α-aminoadipic acidemia. Similarly, C57BL/6J mice have decreased Bckdhb mRNA expression due to an LTR retrotransposon in intron 1 of Bckdhb. This transposable element encodes an alternative exon 1 causing aberrant splicing, decreased total and functional Bckdhb mRNA and decreased BCKDHB protein. Using a targeted metabolomics screen, we also reveal elevated plasma C5-carnitine in 129 substrains. This biochemical phenotype resembles isovaleric acidemia and is caused by an exonic splice mutation in Ivd leading to partial skipping of exon 10 and IVD protein deficiency. In summary, this study identifies three causal variants underlying mild inborn errors of metabolism in commonly used inbred mouse strains.
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Fetal alcohol spectrum disorders (FASD) are prevalent neurodevelopmental disorders. Genetics have been shown to have a role in the severity of alcohol’s teratogenic effects on the developing brain. We previously identified recomb...
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Fetal alcohol spectrum disorders (FASD) are prevalent neurodevelopmental disorders. Genetics have been shown to have a role in the severity of alcohol’s teratogenic effects on the developing brain. We previously identified recombinant inbred BXD mouse strains that show high (HCD) or low cell death (LCD) in the hippocampus following ethanol exposure. The present study aimed to identify gene networks that influence this susceptibility. On postnatal day 7 (3rd-trimester-equivalent), male and female neonates were treated with ethanol (5.0 g/kg) or saline, and hippocampi were collected 7hrs later. Using the Affymetrix microarray platform, ethanol-induced gene expression changes were identified in all strains with divergent expression sets found between sexes. Genes, such as Bcl2l11, Jun, and Tgfb3, showed significant strain-by-treatment interactions and were involved in many apoptosis pathways. Comparison of HCD versus LCD showed twice as many ethanol-induced genes changes in the HCD. Interestingly, these changes were regulated in the same direction suggesting (1) more perturbed effects in HCD compared to LCD and (2) limited gene expression changes that confer resistance to ethanol-induced cell death in LCD. These results demonstrate that genetic background and sex are important factors that affect differential cell death pathways after alcohol exposure during development that could have long-term consequences.
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The genetic relationships between different behaviors used to index the rewarding or reinforcing effects of alcohol are poorly understood. To address this issue, ethanol-induced conditioned place preference (CPP) was tested in a g...
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The genetic relationships between different behaviors used to index the rewarding or reinforcing effects of alcohol are poorly understood. To address this issue, ethanol-induced conditioned place preference (CPP) was tested in a genetically diverse panel of inbred mouse strains, and strain means from this study and other inbred strain studies were used to examine the genetic correlation between CPP and several ethanol-related phenotypes, including activity measures recorded during CPP training and testing. Mice from each strain were exposed to a well-characterized unbiased place conditioning procedure using ethanol doses of 2 or 4 g/kg; an additional group from each strain was exposed to saline alone on all trials. Genotype had a significant effect on CPP, basal locomotor activity, ethanol-stimulated activity, and the effect of repeated ethanol exposure on activity. Correlational analyses showed significant negative genetic correlations between CPP and sweetened ethanol intake and between CPP and test session activity, as well as a significant positive genetic correlation between CPP and chronic ethanol withdrawal severity. Moreover, there was a trend toward a positive genetic correlation between CPP and ethanol-induced conditioned taste aversion. These genetic correlations suggest overlap in the genetic mechanisms underlying CPP and each of these traits. The patterns of genetic relationships suggest a greater impact of ethanol's aversive effects on drinking and a greater impact of ethanol's rewarding effects on CPP. Overall, these data support the idea that genotype influences ethanol's rewarding effect, a factor that may contribute importantly to addictive vulnerability.
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