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At least 109 records · Page 6Linked to original sources

PubMed1998

Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model.

Hirschsprung disease (HSCR, MIM #142623) is a multigenic neurocristopathy (neural crest disorder) characterized by absence of enteric ganglia in a variable portion of the distal colon. Subsets of HSCR individuals also present with neural crest-derived melanocyte deficiencies (Hirschsprung-Waardenburg, HSCR-WS, MIM #277580). Murine models have been instrumental in the identification and analysis of HSCR disease genes. These include mice with deficiencies of endothelin B receptor (Ednrb(s-l); refs 1,2) endothelin 3 (Edn3(ls): refs 1,3) the tyrosine kinase receptor cRet and glial-derived neurotrophic factor. Another mouse model of HSCR disease, Dom, arose spontaneously at the Jackson Laboratory. While Dom/+ heterozygous mice display regional deficiencies of neural crest-derived enteric ganglia in the distal colon, Dom/Dom homozygous animals are embryonic lethal. We have determined that premature termination of Sox10, a member of the SRY-like HMG box family of transcription factors, is responsible for absence of the neural crest derivatives in Dom mice. We demonstrate expression of Sox10 in normal neural crest cells, disrupted expression of both Sox10 and the HSCR disease gene Ednrb in Dom mutant embryos, and loss of neural crest derivatives due to apoptosis. Our studies suggest that Sox10 is essential for proper peripheral nervous system development. We propose SOX10 as a candidate disease gene for individuals with HSCR whose disease does not have an identified genetic origin.

Amino Acid Sequence↗

PubMed2002

Effect of group vs. single housing on phenotypic variance in C57BL/6J mice.

OBJECTIVE: To determine if group housing affects the variance of body composition parameters in a highly inbred mouse strain. RESEARCH METHODS AND PROCEDURES: Thirty 3-week-old male C57BL/6J mice were obtained from the Jackson Laboratory. Fifteen mice were housed individually, and 15 mice were housed in groups of 5/cage. Animals were fed ad libitum and maintained in the same room under a 12:12-hour light/dark photoperiod at 22 degrees C for 9 weeks. Animals were killed, and fat mass, soft-lean tissue mass, bone mineral density (BMD), and bone mineral content (BMC) were determined by DXA. At necropsy, weights of the paired epididymal fat pads, paired retroperitoneal fat pads, right inguinal fat pad, liver, kidneys, paired testes, and seminal vesicles were obtained. RESULTS: Relative to mice housed singly, group-housed mice showed significantly greater variance in percentage of body fat, testes weight, and BMC. Group-housed mice tended to show greater variance in liver weights and BMD. Mice housed singly were smaller, had less soft-lean tissue mass and BMC, and lower BMD when compared with group-housed mice. DISCUSSION: These results suggest that with respect to body composition parameters, mice housed singly are more similar to one another than are group-housed mice, most likely because of a reduction in environmental (predominately behavioral/social) effects. Thus, mice housed singly may be more representative of genotypic effects on body composition than group-housed mice. Whether other inbred strains of mice show similar responses to housing condition is unknown.

Adipose Tissue↗

PubMed1998

A molecular investigation of the obese phenotype in the Aston University strain of ob/ob mice and the Japanese Kuo Kondo mice.

The aim of this work was to determine the role of the ob gene in the obese phenotype observed in the Aston University Strain of ob/ob mouse and the Japanese Kuo Kondo (KK) mouse. After RT-PCR amplification of the ob RNA, the transcript was cloned into the vector pCR3 and three individual clones from each strain were sequenced. It was confirmed that the Aston University strain of ob/ob mice shared the same C-T mutation found in the Jackson Laboratory C57BL/6J ob/ob strain whereas the Japanese KK mice showed wild-type ob gene expression. This study indicates that the ob mutation has survived unchanged following the separation of the two strains of ob/ob mice, and secondly, that the molecular basis of the obese phenotype in the KK mice is not due to mutations in the ob gene.

Animals↗

PubMed1997

Praja1, a novel gene encoding a RING-H2 motif in mouse development.

As part of a cloning strategy to identify genes involved in early mouse liver development we have isolated Praja1, a gene with similar sequences to the Drosophila melanogaster gene goliath (gl) which is involved in the fate of mesodermal cells ultimately forming gut musculatures, fat body, and the heart. Praja1 is a 2.1 kb gene encoding a putative 396 amino acid ORF and includes a COOH-terminal RING-H2 domain. Using the Jackson Laboratory BSS panel, we have localized Praja1 on chromosome X at 36 cM, which may be a candidate gene for mouse sla (sex linked sideroblastic anemia), near the X inactivation center gene, Xist. Northern blot analysis demonstrated three transcripts (3.1, 2.6 and 2.1 kb) in mRNA from adult mouse tissues brain, liver, and kidney as well as in mRNA from developing mouse embryos (days 7, 11, 15 and 17 post coitus, p.c.). In vitro transcription/translation yielded a product with an Mr of 59 kD. Immunohistochemical staining of in vitro liver explant cultures using a heterologous antibody against praja1 demonstrated cytoplasmic staining of cuboidal cells that have hepatocyte morphology and organization. The presence of the RING-H2 domain, a proline-rich region at the COOH-end, and regions rich in acidic amino acids, leads to the hypothesis that the Praja1 product is possibly involved in mediating protein-protein interactions, possibly as part of a protein sorting or transport pathway. This is strengthened by the similarity of Praja1 to rat Neurodap1, whose product has been shown to localize to the endoplasmic reticulum and golgi in brain.

Amino Acid Sequence↗

PubMed2003

Normoblastosis, a murine model for ankyrin-deficient hemolytic anemia, is caused by a hypomorphic mutation in the erythroid ankyrin gene Ank1.

Ankyrin deficiency is one of the most common causes of hereditary spherocytosis in humans. A spontaneous mutation, normoblastosis (Ank1nb), discovered in 1969 in a mouse stock maintained at the Jackson Laboratory, provides an important animal model for these human ankyrin-deficient anemias. Study of this model has led to the finding of multiple isoforms of Ank1 as well as Ank1nb-related pathology in nonerythroid tissues. To enhance the usefulness of this model, we have identified the Ank1nb mutation as the deletion of a guanosine residue in exon 36 of the erythroid ankyrin gene (Ank1). This results in a frame shift that introduces a stop 13 codons downstream and predicts a 157 kDa nb-ankyrin lacking the regulatory domain but including intact membrane- and spectrin-binding domains. By epitope scanning on immunoblots, we show that a previously reported protein (p150) found in nb reticulocytes is the predicted nb-ankyrin. Existing evidence indicates that this protein is functional, making the normoblastosis mutation a hypomorph rather than a null as originally thought. The nb-ankyrin provides an explanation for the milder phenotype displayed by nb/nb animals relative to the murine spectrin-deficient anemias, spherocytosis (Spna1(sph), Spna1(sph-1J), Spna1(sph-2BC), Spna1(sph-DEM)) and jaundiced (Spnb1(ja)), and suggests that truncated ankyrins could be useful in gene replacement therapy.

Alternative Splicing↗

PubMed2000

A metabolic syndrome of hypertension, hyperinsulinaemia and hypercholesterolaemia in the New Zealand obese mouse.

BACKGROUND: New Zealand obese (NZO) mice exhibit a polygenic obesity associated with hyperinsulinaemia and hyperglycaemia. Here we show that the strain presents additional features of a metabolic syndrome, i.e. elevated blood pressure, serum cholesterol and serum triglyceride levels. MATERIALS AND METHODS: A back-cross model of NZO mice with the lean Swiss Jackson Laboratory (SJL) strain was established in order to investigate further the correlation between hypertension, obesity, serum insulin and hyperglycaemia. RESULTS: Systolic blood pressure was significantly elevated at 6 weeks of age and appeared to parallel the weight gain of the animals. Serum insulin levels, presumably reflecting insulin resistance, and systolic blood pressure values were significantly correlated with the body mass index (r2 = 0.707 and 0.486, respectively) in the back-cross mice. In contrast, blood pressure was only weakly correlated with serum insulin (r2 = 0.288) in non-diabetic mice, and was independent of serum insulin levels in diabetic animals. CONCLUSION: The data are consistent with the concept that hypertension and insulin resistance are a characteristic consequence of the genetic constellation leading to obesity in the NZO strain, and that these traits reflect related mechanisms. It appears unlikely, however, that hypertension is a direct consequence of hyperinsulinaemia.

Animals↗

PubMed1991

Do histocompatibility genes influence sex ratio (% males)?

Breeding records for 15 of the 42 C57BL/10SnJ Congenic Histocompatibility Mouse Strains from the Special Mouse Stocks Resource (SMSR) showed three with a significant excess of male offspring. Strain B10.R111(71NS), hereafter R, gave the highest proportion of males (55.68 +/- 0.59% of 7129 newborn) which is significantly more than the proportion of male offspring (49.81 +/- 0.94% of 2853 newborn) from the C57BL/10SnJ progenitor strain, hereafter B. All mice in the SMSR colonies were fed Old Guildford 96 and Old Guildford 96W liberally on alternate weeks. Breeding females of B and R strains were established in a research colony at the Jackson Laboratory under conditions similar to those in SMSR except that they were fed Wayne Sterilizable Rodent Blox. More than 5000 inbred, hybrid and backcross fetuses were examined but no evidence of an excess of males was found. Also, there were no strain differences in the neonatal data. However, the sex ratio of the 4396 neonates was just significantly higher (P less than 0.05) than that of the fetuses, indicating some perinatal loss of females. An even greater loss of females was most probably the cause of the high sex ratios in the preliminary and follow-up surveys of SMSR R mice, which we ascribe to an interaction between the H-2 haplotype of the R strain, or a gene linked thereto, and the Old Guildford diet that is unfavourable to female survival. The sex ratio of fetuses agreed so closely with the Mendelian expectation as to indicate that the primary sex ratio was 50% males and that the R strain is not a model for the human male bias. There were no hermaphrodites or twins and the sex ratio of the fetuses in litters without resorptions was normal. These findings emphasize the variability of presumptive secondary sex ratios.

Animals↗

PubMed2001

Active site mutant transgene confers tolerance to human beta-glucuronidase without affecting the phenotype of MPS VII mice.

Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is an autosomal recessive lysosomal storage disorder due to an inherited deficiency of beta-glucuronidase. A naturally occurring mouse model for this disease was discovered at The Jackson Laboratory and shown to be due to homozygosity for a 1-bp deletion in exon 10 of the gus gene. The murine model MPS VII (gus(mps/mps)) has been very well characterized and used extensively to evaluate experimental strategies for lysosomal storage diseases, including bone marrow transplantation, enzyme replacement therapy, and gene therapy. To enhance the value of this model for enzyme and gene therapy, we produced a transgenic mouse expressing the human beta-glucuronidase cDNA with an amino acid substitution at the active site nucleophile (E540A) and bred it onto the MPS VII (gus(mps/mps)) background. We demonstrate here that the mutant mice bearing the active site mutant human transgene retain the clinical, morphological, biochemical, and histopathological characteristics of the original MPS VII (gus(mps/mps)) mouse. However, they are now tolerant to immune challenge with human beta-glucuronidase. This "tolerant MPS VII mouse model" should be useful for preclinical trials evaluating the effectiveness of enzyme and/or gene therapy with the human gene products likely to be administered to human patients with MPS VII.

Animals↗

PubMed1978

Presence of anti-Sm reactivity in autoimmune mouse strains.

The investigation of the fine specificities of antinuclear antibodies (ANAs) has been fruitful in terms of the nosology and immunopathogenesis of human autoimmune syndromes. Particular reactivities serve as "markers," in that patients with certain syndromes have a much higher incidence of such ANAs than do patients with other diseases. In this category is the almost exclusive against the nuclear acidic protein Sm. Reactivity to Sm can be detected by precipitation in agar, complement fixation, or passive hemagglutination (1,2). Autoimmune mouse strains have also provided a fertile field for the investigation of the basic phenomena of self-activity. In particular, the NZB strain and its hybrid NZB x NZW have been considered excellent models for human SLE and have therefore been studied in great detail (3,4). In addition, Murphy et al at The Jackson Laboratory, Bar Harbor, Maine, have developed several new inbred mouse strains that spontaneously develop SLE-like syndromes (5,6). These are the BXSB strain, which has a male dominant disease characterized by little antiative DNA antibody; the MRL/1, which develops massive, nonmalignant lymphadenopathy, associated with enormous increases in serum immunoglobulin levels and fulminant renal disease; and the MRL/n, which does not develop SLE-like disease until well into the 2nd yr of life, but like the MRL/1 develops high titers of ANA and fatal glomerulonephritis. The MRL/1 differs from MRL/n in only about 10 percent of its genome, including the gene responsible for the MRL/1's lymphoproliferation. In the current study, we have used the technique of double immunodiffusion (ID) in agarose with standard human reference sera (of known ANA specificity) to survey a large number of mice from the NZB x NZW, MRL/1, MRL/n, BXSB, and other strains. We report here the finding of the anti-Sm marker" antibody almost uniquely in MRL/1 and MRL/n animals. These two related strains may serve as experimental models to explore the mechanism stimulating the production of this unique autoantibody in SLE.

Animals↗

PubMed1980

Incidence and specificities of IgA and IgM anti-AgG autoantibodies in various mouse strains and colonies.

Mice, greater than 20 wk old, were tested for the presence of anti-IgG autoantibodies by agglutination and radioimmunoassay. IgA and IgM anti-IgG were found in the 129/Sv, C57BL/6, and DBA/2 strains from the local colony at the International Institute of Cellular and Molecular Pathology (ICP), at the Institut Pasteur de Paris (IP), and in the endotoxin-resistant C3H/He strain of ICP. These strains were negative at Iffa Credo (IC), and at The Jackson Laboratory (JL). Among 33 strains from the latter colony, 129/J, AKR/J, CBA/J, C57L/J, and NZB/BinJ were positive. All were specific pathogen-free and, excepting the NZB/BinJ, are not known to develop systemic autoimmune disorders. These differences between colonies suggest an influence of the environment on the production of anti-IgG. Evidence for the role of an infectious agent was provided by the fact that germ-free DBA/2 were negative in contrast to their SPF relatives. Strains which were positive at ICP and IP for anti-IgG had four-times higher serum levels of total IgA and two-times higher levels of total IgG than the corresponding negative strains from IC and JL. The anti-IgG titers differed markedly from one strain to the other in the same environment; e.g., in mice from ICP, BALB/c mice produced 40-times less anti-IgG than 129/Sv. IgA anti-IgG occurred only in high producers of anti-IgG. In these animals, the proportion of IgA vs. IgM anti-IgG was very different from one group to the other; C57BL/6 had mainly IgM anti-IgG, DBA/2 mainly IgA anti-IgG, and 129/Sv both IgM and IgA anti-IgG. The IgA anti-IgG from 129/Sv, 129/J, NZB/BinJ, C57L/J, DBA/2, and C3H/He had restricted hetero-, iso-, and allotypic specificities. It reacted only with mouse IgGa2, but not with the Ig-1b allotype. C57BL/6 also had IgA anti-IgG with a narrow specificity, but directed against IgG1 without allotypic restriction. In contrast to the specificity of IgA anti-IgG, the antibody activity of IgM anti-IgG was much broader, except in the 129/Sv and 129/J strains where IgM anti-IgG shared the same narrow specificity with IgA.

Agglutination Tests↗

PubMed2001

A comparison of microarray databases.

Microarray technology has become one of the most important functional genomics technologies. A proliferation of microarray databases has resulted. It can be difficult for researchers exploring this technology to know which bioinformatics systems best meet their requirements. In order to obtain a better understanding of the available systems, a survey and comparative analysis of microarray databases was undertaken. The survey included databases that are currently available, as well as databases that should become available in early 2001. Databases fall into three categories: (i) those that can be installed locally, (ii) those available for public data submission and (iii) those available for public query. Developers of microarray gene-expression databases were asked questions regarding the scope and availability of their database, its system requirements, its future compliance with MGED (Microarray Gene Expression Database) standards, and its associated analytical tools. Participants included AMAD (Stanford/Berkeley/UCSF), ArrayExpress (EBI), ChipDB (MIT/Whitehead), GeneX (NCGR), GeNet (Silicon Genetics), GeneDirector (BioDiscovery), GEO (NCBI), GXD (Jackson Laboratory), mAdb (NCI), maxdSQL (University of Manchester), NOMAD (UCSF), RAD (University of Pennsylvania) and SMD (Stanford University). Other database developers were contacted but data was not available at the time of manuscript preparation. Each database fulfils a different role, reflecting the widely varying needs of microarray users.

Animals↗

PubMed2002

A bioinformatics tool to select sequences for microarray studies of mouse models of oncogenesis.

UNLABELLED: One of the challenges to the effective utilization of cDNA microarray analysis in mouse models of oncogenesis is the choice of a critical set of probes that are informative for human disease. Given the thousands of genes with a potential role in human oncogenesis and the hundreds of thousands of mouse sequences available for use as probes, selection of an informative set of mouse probes can be an overwhelming task. We have developed a web based sequence mining tool using DataBase Independent (DBI) Perl to annotate publicly available sequences. The Mouse Oncochip Design Tool uses the Mouse Genome Database (MGD) developed and maintained by the Jackson Laboratories for mouse DNA sequences. There are over 380 000 sequences in their database. The output list has been ordered to present the genes more likely to be informative in a mouse model of human cancer using a candidate set of oncogenes to order the list. Mouse sequences that represent genes that are homologous with a member of a human oncogene set are listed first. In addition it provides a set of links for information on clone source gene function. CONTACT: http://nciarray.nci.nih.gov/cgi-bin/me/mouse_design.cgi

Animals↗

PubMed1998

Characterization of lpd (lipid defect): a novel mutation on mouse chromosome 16 associated with a defect in triglyceride metabolism.

Recent epidemiological studies have identified plasma triglyceride as a risk factor for atherogenesis. We have generated a mouse transgenic line that carries a recessive mutation designated lpd (lipid defect). Homozygous lpd mice develop as runts and die by age 10-15 days with striking liver pathology characterized by the presence of numerous lipid-containing vacuoles and extensive accumulation of triglycerides. Cloning of the mutant insertion locus and the wild-type lpd locus have revealed a duplication of host genomic sequences at the site of integration. Mapping of the lpd locus with the Jackson Laboratory BSS interspecific backcross panel of (C57BL/6JEi x SPRET/Ei) F1 x SPRET/Ei placed the lpd locus to the distal part of chromosome 16. These observations suggest that the transgene disrupts a putative gene at the lpd locus and that lpd is a novel locus related to triglyceride metabolism. The lpd mutant mice may serve as models for human disorders of fatty livers or hypertriglyceridemia.

Animals↗

PubMed1999

Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome.

A spontaneous mutation causing deafness and circling behavior was discovered in a C3H/HeJ colony of mice at the Jackson Laboratory. Pathological analysis of mutant mice revealed gross morphological abnormalities of the inner ear, and also dysmorphic or missing kidneys. The deafness and abnormal behavior were shown to be inherited as an autosomal recessive trait and mapped to mouse chromosome 1 near the position of the Eya1 gene. The human homolog of this gene, EYA1, has been shown to underly branchio-oto-renal (BOR) syndrome, an autosomal dominant disorder characterized by hearing loss with associated branchial and renal anomalies. Molecular analysis of the Eya1 gene in mutant mice revealed the insertion of an intracisternal A particle (IAP) element in intron 7. The presence of the IAP insertion was associated with reduced expression of the normal Eya1 message and formation of additional aberrant transcripts. The hypomorphic nature of the mutation may explain its recessive inheritance, if protein levels in homozygotes, but not heterozygotes, are below a critical threshold needed for normal developmental function. The new mouse mutation is designated Eya1(bor) to denote its similarity to human BOR syndrome, and will provide a valuable model for studying mutant gene expression and etiology.

Animals↗

PubMed2005

Discovery genetics: serendipity in basic research.

The role of serendipity in science has no better example than the discovery of spontaneous mutations that leads to new mouse models for research. The approach of finding phenotypes and then carrying out genetic analysis is called forward genetics. Serendipity is a key component of discovering and developing mice with spontaneous mutations into animal models of human disease. In this article, the role of serendipity in discovering and developing mouse models is described within a program at The Jackson Laboratory that capitalizes on serendipitous discoveries in large breeding colonies. Also described is how any scientists working with mice can take advantage of serendipitous discoveries as a research strategy to develop new models. Spontaneous mutations cannot be planned but happen in all research mouse colonies and are discovered as unexpected phenotypes. The alert scientist or technician can rationally exploit such chance observations to create new research opportunities.

Animals↗

PubMedDate not supplied

A new allelic series for the underwhite gene on mouse chromosome 15.

A new allelic series at the underwhite gene is described. Three of the alleles in the series--uw, uwd, and Uwdbr--arose as spontaneous mutations on different genetic backgrounds at The Jackson Laboratory. We report here the visible phenotypes and dominance hierarchy of these alleles, all of which are defined by a reduction of pigmentation in both eye and coat color. Electron microscopic analysis of retinal epithelium suggests that the primary defect is in the melanosome. The degree of severity of melanosome anomalies in the retina correlates with the degree of hypopigmentation in the coat. The perturbed gene and its gene product are unknown. We show that the uw locus is genetically distinct from Myo10, a suggested candidate gene for this mutation.

Alleles↗

PubMed1975

Alpha fetoprotein: effect of heterologous antiserum on hepatoma cells in vitro.

Hepatoma cells derived from The Jackson Laboratory mouse hepatoma BW7756 synthesized alpha fetoprotein (AFP) in vitro. The AFP was immunologically identical to that circulating in the sera of hepatoma-bearing mice. An in vitro cytotoxic effect of rabbit antiserum to AFP was studied in hepatoma cells obtained both from fresh cell suspensions and short-term cell culture. The use of intact and/or inactivated anti-AFP serum inhibited the growth of the AFP-producing cells. The cytotoxic effects of the antiserum depended on exposure time and serum concentration. The cytotoxicity was complement independent, as demonstrated by studies with heat-deactivated serum devoid of extrinsic complement. The control target cells included fresh cell suspensions of normal mouse liver and mouse muscle fibroblasts grown in short-term culture. Specificity of the antisera for the target cells was demonstrated by absorption with purified mouse AFP. The results could be explained by the presence of AFP on the hepatoma cell surface.

Animals↗

PubMed1985

Attenuation of exogenous murine mammary tumor virus virulence in the C3H/HeJ mouse substrain bearing the Lps mutation.

A major change in mammary tumor incidence (MTI) and latency has occurred in the C3H/HeJ mouse substrain maintained at The Jackson Laboratory. The average time required for 50% of the C3H/HeJ mice to develop a mammary tumor changed from 40 weeks of age to the current 61 weeks of age. This 61-week median MTI in the C3H/HeJ substrain is significantly different from the less than 40-week median MTI seen in other C3H substrains infected with an exogenous milk-transmitted murine mammary tumor virus (MuMTV). The median MTI of over 80 weeks in MuMTV-negative C3H substrains also is significantly longer than that seen in C3H/HeJ mice. Although the median MTI for the C3H/HeJ substrain has changed significantly, the continued presence of an exogenous MuMTV in C3H/HeJ mice was confirmed by the presence of high levels of gp52 antigen in the milk of lactating females. Presence of an exogenous MuMTV in C3H/HeJ female mice also was confirmed by their ability to pass their exogenous MuMTV(HeJ) via their milk to exogenous MuMTV-negative BALB/cByJ, C3H, or C3H hybrid mice. These foster-nursed mice exhibited the reduced tumor frequency and the increased median MTI seen in their C3H/HeJ foster mothers. The change in tumor incidence and latency in the C3H/HeJ substrain is not due to the loss of the exogenous MuMTV but to the occurrence of an attenuated MuMTV. Selection of this attenuated MuMTV may be related to the presence of the Lps mutation that occurred during the same time period that the MTI changed in the C3H/HeJ substrain.

Animals↗