scholarly journals Involvement of T1R3 in calcium-magnesium taste

2008 ◽  
Vol 34 (3) ◽  
pp. 338-348 ◽  
Author(s):  
Michael G. Tordoff ◽  
Hongguang Shao ◽  
Laura K. Alarcón ◽  
Robert F. Margolskee ◽  
Bedrich Mosinger ◽  
...  
Keyword(s):  
Strain Difference ◽  
Receptor Gene ◽  
Inbred Mouse ◽  
Taste Receptor ◽  
Mouse Strains ◽  
Chorda Tympani Nerve ◽  
Wild Type ◽  
A Genome ◽  
Calcium Magnesium ◽  
Calcium And Magnesium

Calcium and magnesium are essential for survival but it is unknown how animals detect and consume enough of these minerals to meet their needs. To investigate this, we exploited the PWK/PhJ (PWK) strain of mice, which, in contrast to the C57BL/6J (B6) and other inbred strains, displays strong preferences for calcium solutions. We found that the PWK strain also has strong preferences for MgCl2 and saccharin solutions but not representative salty, sour, bitter, or umami taste compounds. A genome scan of B6 × PWK F2 mice linked a component of the strain difference in calcium and magnesium preference to distal chromosome 4. The taste receptor gene, Tas1r3, was implicated by studies with 129.B6ByJ- Tas1r3 congenic and Tas1r3 knockout mice. Most notably, calcium and magnesium solutions that were avoided by wild-type B6 mice were preferred (relative to water) by B6 mice null for the Tas1r3 gene. Oral calcium elicited less electrophysiological activity in the chorda tympani nerve of Tas1r3 knockout than wild-type mice. Comparison of the sequence of Tas1r3 with calcium and saccharin preferences in inbred mouse strains found 1) an inverse correlation between calcium and saccharin preference scores across primarily domesticus strains, which was associated with an I60T substitution in T1R3, and 2) a V689A substitution in T1R3 that was unique to the PWK strain and thus may be responsible for its strong calcium and magnesium preference. Our results imply that, in addition to its established roles in the detection of sweet and umami compounds, T1R3 functions as a gustatory calcium-magnesium receptor.

scholarly journals Genetics of sweet taste preferences

2002 ◽  
Vol 74 (7) ◽  
pp. 1135-1140 ◽  
Author(s):  
Alexander A. Bachmanov ◽  
Danielle R. Reed ◽  
Xia Li ◽  
Gary K. Beauchamp
Keyword(s):  
Positional Cloning ◽  
Inbred Mouse ◽  
Taste Receptor ◽  
Sweet Taste ◽  
Mouse Strains ◽  
Taste Receptors ◽  
Chromosome 4 ◽  
Sweet Taste Receptor ◽  
Distal Chromosome ◽  
Allelic Differences

Inbred mouse strains display marked differences in avidity for sweet solutions due in part to genetic differences among strains. Using several techniques, we have located a number of regions throughout the genome that influence sweetener acceptance. One prominent locus regulating differences in sweetener preferences among mouse strains is the saccharin preference (Sac) locus on distal chromosome 4. Afferent responses of gustatory nerves to sweeteners also vary as a function of allelic differences in the Sac locus, suggesting that this gene may encode a sweet taste receptor. Using a positional cloning approach, we identified a gene (Tas1r3) encoding the third member of the T1R family of putative taste receptors, T1R3. Introgression by serial back-crossing of a chromosomal fragment containing the Tas1r3 allele from the high sweetener-preferring strain onto the genetic background of the low sweetener-preferring strain rescued its low sweetener-preference phenotype. Tas1r3 has two common haplotypes, one found in mouse strains with elevated sweetener preference and the other in strains relatively indifferent to sweeteners. This study, in conjunction with complimentary recent studies from other laboratories, provides compelling evidence that Tas1r3 is equivalent to the Sac locus and that the T1R3 receptor (when co-expressed with taste receptor T1R2) responds to sweeteners. However, other sweetness receptors may remain to be identified.

scholarly journals SJL/J Mice Are Highly Susceptible to Infection by Mouse Adenovirus Type 1

2001 ◽  
Vol 75 (24) ◽  
pp. 12039-12046 ◽  
Author(s):  
Katherine R. Spindler ◽  
Lei Fang ◽  
Martin L. Moore ◽  
Gwen N. Hirsch ◽  
Corrie C. Brown ◽  
...  
Keyword(s):  
Inbred Mouse ◽  
Adenovirus Type ◽  
Wild Type Virus ◽  
Mouse Strains ◽  
Wild Type ◽  
Viral Loads ◽  
Sublethal Doses ◽  
The Brain ◽  
Lethal Doses

ABSTRACT Mouse adenovirus type 1 (MAV-1) targets endothelial and monocyte/macrophage cells throughout the mouse. Depending on the strain of mouse and dose or strain of virus, infected mice may survive, become persistently infected, or die. We surveyed inbred mouse strains and found that for the majority tested the 50% lethal doses (LD50s) were >104.4 PFU. However, SJL/J mice were highly susceptible to MAV-1, with a mean LD50 of 10−0.32 PFU. Infected C3H/HeJ (resistant) and SJL/J (susceptible) mice showed only modest differences in histopathology. Susceptible mice had significantly higher viral loads in the brain and spleen at 8 days postinfection than resistant mice. Infection of primary macrophages or mouse embryo fibroblasts from SJL/J and C3H/HeJ mice gave equivalent yields of virus, suggesting that a receptor difference between strains is not responsible for the susceptibility difference. When C3H/HeJ mice were subjected to sublethal doses of gamma irradiation, they became susceptible to MAV-1, with an LD50 like that of SJL/J mice. Antiviral immunoglobulin G (IgG) levels were measured in susceptible and resistant mice infected by an early region 1A null mutant virus that is less virulent that wild-type virus. The antiviral IgG levels were high and similar in the two strains of mice. Taken together, these results suggest that immune response differences may in part account for differences in susceptibility to MAV-1 infection.

Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in aSlc39a8-transgenic mouse line

2007 ◽  
Vol 292 (4) ◽  
pp. C1523-C1535 ◽  
Author(s):  
Bin Wang ◽  
Scott N. Schneider ◽  
Nadine Dragin ◽  
Kuppuswami Girijashanker ◽  
Timothy P. Dalton ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Proximal Tubule ◽  
Positional Cloning ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Tubular Damage ◽  
Recessive Trait ◽  
Apical Surface ◽  
Wild Type ◽  
Transgenic Mouse Line

Resistance to cadmium (Cd)-induced testicular necrosis is an autosomal recessive trait defined as the Cdm locus. Using positional cloning, we previously identified the Slc39a8 (encoding an apical-surface ZIP8 transporter protein) as the gene most likely responsible for the phenotype. In situ hybridization revealed that endothelial cells of the testis vasculature express high ZIP8 levels in two sensitive inbred mouse strains and negligible amounts in two resistant strains. In the present study, we isolated a 168.7-kb bacterial artificial chromosome (BAC), carrying only the Slc39a8 gene, from a Cd-sensitive 129/SvJ BAC library and generated BAC-transgenic mice. The BTZIP8-3 line, having three copies of the 129/SvJ Slc39a8 gene inserted into the Cd-resistant C57BL/6J genome (having its normal two copies of the Slc39a8 gene), showed tissue-specific ZIP8 mRNA expression similar to wild-type mice, mainly in lung, testis, and kidney. The ∼2.5-fold greater expression paralleled the fact that the BTZIP8-3 line has five copies, whereas wild-type mice have two copies, of the Slc39a8 gene. The ZIP8 mRNA and protein localized especially to endothelial cells of the testis vasculature in BTZIP8-3 mice. Cd treatment reversed Cd resistance (seen in nontransgenic littermates) to Cd sensitivity in BTZIP8-3 mice; reversal of the testicular necrosis phenotype confirms that Slc39a8 is unequivocally the Cdm locus. ZIP8 also localized specifically to the apical surface of proximal tubule cells in the BTZIP8-3 kidney. Cd treatment caused acute renal failure and signs of proximal tubular damage in the BTZIP8-3 but not nontransgenic littermates. BTZIP8-3 mice should be a useful model for studying Cd-induced disease in kidney.

scholarly journals Toll-like receptor 4-mediated respiratory syncytial virus disease and lung transcriptomics in differentially susceptible inbred mouse strains

2019 ◽  
Vol 51 (12) ◽  
pp. 630-643 ◽  
Author(s):  
Jacqui Marzec ◽  
Hye-Youn Cho ◽  
Monica High ◽  
Zachary R. McCaw ◽  
Fernando Polack ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Virus Disease ◽  
Inbred Mouse ◽  
Dominant Negative ◽  
Epidermal Differentiation ◽  
Mouse Strains ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) causes severe lower respiratory tract disease in infants, young children, and susceptible adults. The pathogenesis of RSV disease is not fully understood, although toll-like receptor 4 (TLR4)-related innate immune response is known to play a role. The present study was designed to determine TLR4-mediated disease phenotypes and lung transcriptomics and to elucidate transcriptional mechanisms underlying differential RSV susceptibility in inbred strains of mice. Dominant negative Tlr4 mutant (C3H/HeJ, HeJ, Tlr4Lps-d) and its wild-type (C3H/HeOuJ, OuJ, Tlr4Lps-n) mice and five genetically diverse, differentially responsive strains bearing the wild-type Tlr4Lps-n allele were infected with RSV. Bronchoalveolar lavage, histopathology, and genome-wide transcriptomics were used to characterize the pulmonary response to RSV. RSV-induced lung neutrophilia [1 day postinfection (pi)], epithelial proliferation (1 day pi), and lymphocytic infiltration (5 days pi) were significantly lower in HeJ compared with OuJ mice. Pulmonary RSV expression was also significantly suppressed in HeJ than in OuJ. Upregulation of immune/inflammatory ( Cxcl3, Saa1) and heat shock protein ( Hspa1a, Hsph1) genes was characteristic of OuJ mice, while cell cycle and cell death/survival genes were modulated in HeJ mice following RSV infection. Strain-specific transcriptomics suggested virus-responsive ( Oasl1, Irg1, Mx1) and epidermal differentiation complex ( Krt4, Lce3a) genes may contribute to TLR4-independent defense against RSV in resistant strains including C57BL/6J. The data indicate that TLR4 contributes to pulmonary RSV pathogenesis and activation of cellular immunity, the inflammasome complex, and vascular damage underlies it. Distinct transcriptomics in differentially responsive Tlr4-wild-type strains provide new insights into the mechanism of RSV disease and potential therapeutic targets.

Two Mouse Genetic Models of Thrombocytopenia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1108-1108 ◽  
Author(s):  
E. Ricky Chan ◽  
Heather Lavender ◽  
Karrie Trevarthen ◽  
Peter Haviernik ◽  
Kevin D. Bunting ◽  
...  
Keyword(s):  
Autoimmune Disorder ◽  
Snp Markers ◽  
Chromosome 8 ◽  
Mouse Strains ◽  
Loss Of Function ◽  
Wild Type ◽  
Genome Wide ◽  
A Genome ◽  
Underlying Causes ◽  
Candidate Interval

Abstract Thrombocytopenia is a disorder in which there is a low level of circulating platelets. There are two main underlying causes; a hematopoietic defect in which there is a decreased production of platelet cells or an autoimmune disorder in which platelets are actively destroyed. Two mutant mouse strains have been obtained from the mutagenesis program at The Heart, Lung, Blood and Sleep Disorders Center at The Jackson Laboratory that each exhibit a dramatic decrease in the level of platelets in comparison to the C57BL/6J wild-type strain making them potentially valuable models for thrombocytopenia. The mutations were crossed to BALB/cByJ and to 129Sv/ImJ and an F2 intercross strategy was used to map the mutation in each strain. Candidate gene sequencing of strain HLB219 revealed a point mutation in the Mpl gene on chromosome 4, which encodes the thrombopoietin (TPO) receptor. This mutation causes an amino acid change from a conserved cysteine to an arginine at codon 40. This ligand-receptor complex plays a pivotal role in megakaryocyte proliferation and maturation and platelet production. The mutation in HLB219 is consistent with other recessive loss-of-function mutations in Mpl that cause hematopoietic defects and thrombocytopenia. HLB219 homozygotes have an elevated circulating TPO level and decreased numbers of hematopoietic progenitors in a colony formation unit (CFU) assay. A competitive repopulation assay showed that HLB219 bone marrow is unable to contribute to hematopoiesis in a lethally-irradiated mouse recipient. Interestingly, HLB219/C57BL/6J heterozygotes show a unique overdominance effect in which platelet levels are elevated compared to wild-type C57BL/6J mice despite having normal TPO levels and reduced megakaryocyte levels in the CFU assay. The mutation in the second mouse model of thrombocytopenia, strain HLB381, has been mapped using a genome-wide linkage scan of 50 F2 intercross progeny. The candidate interval has been narrowed by screening >240 F2 progeny with additional microsatellite and SNP markers. The candidate interval spans 4.2 megabases at the centromeric end of chromosome 8. In contrast to results obtained with HLB219, a competitive repopulation assay demonstrated that HLB381 has normal hematopoietic capability. However, chimeric mice from these assays have low platelet levels, indicating that an autoimmune defect may be responsible for the phenotype. Furthermore, HLB381 mice have normal levels of circulating TPO. Current studies are focused on determining whether HLB381 may serve as a heritable model for idiopathic thrombocytopenic purpura (ITP), an autoimmune disorder.

scholarly journals In silico QTL mapping of basal liver iron levels in inbred mouse strains

2011 ◽  
Vol 43 (3) ◽  
pp. 136-147 ◽  
Author(s):  
Stela McLachlan ◽  
Seung-Min Lee ◽  
Teresa M. Steele ◽  
Paula L. Hawthorne ◽  
Matthew A. Zapala ◽  
...  
Keyword(s):  
Iron Status ◽  
Inbred Mouse ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Chromosome 11 ◽  
Liver Iron ◽  
Functional Studies ◽  
A Genome ◽  
Genotype Information ◽  
Diferric Transferrin

Both iron deficiency and iron excess are detrimental in many organisms, and previous studies in both mice and humans suggest that genetic variation may influence iron status in mammals. However, these genetic factors are not well defined. To address this issue, we measured basal liver iron levels in 18 inbred strains of mice of both sexes on a defined iron diet and found ∼4-fold variation in liver iron in males (lowest 153 μg/g, highest 661 μg/g) and ∼3-fold variation in females (lowest 222 μg/g, highest 658 μg/g). We carried out a genome-wide association mapping to identify haplotypes underlying differences in liver iron and three other related traits (copper and zinc liver levels, and plasma diferric transferrin levels) in a subset of 14 inbred strains for which genotype information was available. We identified two putative quantitative trait loci (QTL) that contain genes with a known role in iron metabolism: Eif2ak1 and Igf2r. We also identified four putative QTL that reside in previously identified iron-related QTL and 22 novel putative QTL. The most promising putative QTL include a 0.22 Mb region on Chromosome 7 and a 0.32 Mb region on Chromosome 11 that both contain only one candidate gene, Adam12 and Gria1, respectively. Identified putative QTL are good candidates for further refinement and subsequent functional studies.

scholarly journals Genetic Influences on the End-Stage Effector Phase of Arthritis

2001 ◽  
Vol 194 (3) ◽  
pp. 321-330 ◽  
Author(s):  
Hong Ji ◽  
Dominique Gauguier ◽  
Koichiro Ohmura ◽  
Antonio Gonzalez ◽  
Veronique Duchatelle ◽  
...  
Keyword(s):  
Gene Dosage ◽  
Inbred Mouse ◽  
Cell Receptor ◽  
Supplementary Information ◽  
Mouse Strains ◽  
Knock Out ◽  
Gene Dosage Effects ◽  
Effector Phase ◽  
A Genome ◽  
End Stage

K/B×N T cell receptor transgenic mice are a model of inflammatory arthritis, most similar to rheumatoid arthritis, that is critically dependent on both T and B lymphocytes. Transfer of serum, or just immunoglobulins, from arthritic K/B×N animals into healthy recipients provokes arthritis efficiently, rapidly, and with high penetrance. We have explored the genetic heterogeneity in the response to serum transfer, thereby focussing on the end-stage effector phase of arthritis, leap-frogging the initiating events. Inbred mouse strains showed clear variability in their responses. A few were entirely refractory to disease induction, and those which did develop disease exhibited a range of severities. F1 analyses suggested that in most cases susceptibility was controlled in a polygenic additive fashion. One responder/nonresponder pair (C57Bl/6 × NOD) was studied in detail via a genome scan of F2 mice; supplementary information was provided by the examination of knock-out and congenic strains. Two genomic regions that are major, additive determinants of the rapidity and severity of K/B×N serum-transferred arthritis were highlighted. Concerning the first region, on proximal chromosome (chr)2, candidate assignment to the complement gene C5 was confirmed by both strain segregation analysis and functional data. Concerning the second, on distal chr1, coinciding with the Sle1 locus implicated in susceptibility to lupus-like autoimmune disease, a contribution by the fcgr2 candidate gene was excluded. Two other regions, on chr12 and chr18 may also contribute to susceptibility to serum-transferred arthritis, albeit to a more limited degree. The contributions of these loci are additive, but gene dosage effects at the C5 locus are such that it largely dominates. The clarity of these results argues that our focus on the terminal effector phase of arthritis in the K/B×N model will bear fruit.

Genetic strain differences in platelet aggregation of laboratory mice

2006 ◽  
Vol 95 (01) ◽  
pp. 159-165 ◽  
Author(s):  
Hideki Ito ◽  
Yukio Kimura ◽  
Toshiki Sudo
Keyword(s):  
Platelet Aggregation ◽  
Knockout Mice ◽  
Strain Difference ◽  
Inbred Mouse ◽  
Laboratory Mouse ◽  
Physiological Role ◽  
Strain Differences ◽  
Mouse Strains ◽  
Laboratory Mice

SummaryTo investigate the physiological role of novel genes and proteins in platelet activation, various knockout mice have been produced. A number of standard inbred mouse strains each possessing genetically unique characters such as high tumor generation, hyperglycemia or hyperlipidemia, have been bred. In breeding knockout mice for investigation of specific physiological functions, appropriate selection of parental or backcross strains is necessary. Thus, examination of strain-specific platelet characteristics is important. In the present study, platelet aggregation responses of 13 laboratory mouse strains, 129/Sv, A, AKR, BALB/c, C3H/He, C57BL/6J, CBA, DBA/1, DBA/2, ddY, FVB, ICR, and NZW, and the diabetic strain C57BL/KsJ db/db, were compared. Marked strain differences were observed inADP- and collagen-induced platelet aggregation. The highest responses with both were seen in AKR/J and NZW/N, whereas the lowest were seen in DBA/2 and DBA/1.There was a 5-fold difference in the platelet aggregation threshold index (PATI) for ADP-induced PRP aggregation between AKR/J (0.6 µM) and DBA/2 (3.0 µM). With whole blood aggregation, the highest response was seen in AKR, whereas the lowest was seen in DBA/2 and DBA/1. The present study demonstrated that there is considerable strain difference in platelet aggregation among laboratory mice, which should be taken into account in backcrossing knockout strains.

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