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Results for “Mice, Transgenic”

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At least 91 records · Page 5Linked to original sources

PubMed1995

Abnormal B-cell function in HTLV-I-tax transgenic mice.

Transgenic mice that carry the HTLV-I Tax gene develop an exocrinopathy with some similarities to Sjoegren's syndrome. Our experiments reveal that these mice have lymphadenopathy and splenomegaly composed primarily of B lymphocytes, as well as abnormal levels of secreted immunoglobulins. To gain insight into whether the lymphadenopathy manifested by these transgenic mice was the result of induction of cytokines by Tax, we utilized cell lines from these mice to study in vitro B-cell responses. Conditioned media (CM) derived from the cell lines caused B-cells to proliferate when a second signal, surface Ig cross-linking, was provided. The CM also caused a marked enhancement of IgM secretion by spleen cells or by purified B-cells treated with supplemental cytokines. The B-cell proliferative response and enhanced IgM secretion have not been attributed to a known cytokine. These results suggest that the CM from the cell lines contain a factor(s) involved in novel pathways of B-cell growth and differentiation that may participate in the pathologic development of autoimmune disease.

Animals↗

PubMed1990

Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice.

Transgenic mice containing a human fetal (gamma-) or adult (beta-) globin gene linked to the beta-globin gene locus activation region (LAR) express the gene throughout development. By contrast, transgenic mice containing LAR linked to both a fetal and an adult globin gene display the normal developmental switch from fetal to adult gene expression. This suggests that the human fetal-to-adult globin gene switch is controlled through a mutually exclusive interaction between LAR and either the gamma- or beta-globin gene, resulting in the expression of only one gene at any given moment.

Animals↗

PubMed2005

Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice.

Transgenic mice overexpressing the P301L mutant human tau protein exhibit an accumulation of hyperphosphorylated tau and develop neurofibrillary tangles. The consequences of tau pathology were investigated here by proteomics followed by functional analysis. Mainly metabolism-related proteins including mitochondrial respiratory chain complex components, antioxidant enzymes, and synaptic proteins were identified as modified in the proteome pattern of P301L tau mice. Significantly, the reduction in mitochondrial complex V levels in the P301L tau mice revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) brains. Functional analysis demonstrated a mitochondrial dysfunction in P301L tau mice together with reduced NADH-ubiquinone oxidoreductase activity and, with age, impaired mitochondrial respiration and ATP synthesis. Mitochondrial dys-function was associated with higher levels of reactive oxygen species in aged transgenic mice. Increased tau pathology as in aged homozygous P301L tau mice revealed modified lipid peroxidation levels and the up-regulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward beta-amyloid (Abeta) peptide insult, suggesting a synergistic action of tau and Abeta pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Abeta.

Alzheimer Disease↗

PubMed1995

Membrane expression of HLA-Cw4 free chains in activated T cells of transgenic mice.

Transgenic mice were produced in which human HLA-Cw4 is stably integrated, behaves as a single Mendelian trait, and, being under the transcriptional control of human CD2, is selectively and efficiently expressed in T lymphocytes. These mice were used as a model system to determine whether HLA-type C molecules can be exposed on the surface of activated lymphocytes as free heavy chains, non-associated with beta2-microglobulin (beta2m). In our transgenic mice we could identify HLA-Cw4 molecules either as free chains or as beta2m-associated molecules by the use of monoclonal antibodies specific for either conformation of HLA class I and nonreactive to mouse H2 molecules. Resting mouse lymphocytes were shown by western transfer analysis to contain sizeable amounts of HLA-Cw4 free chains, but they exposed on their surface HLA-Cw4 only in association with beta2m, as indicated by flow cytometric measurements. Conversely, where the content of total HLA-Cw4 was increased, lectin-activated mouse lymphocytes exposed on their outer cell membrane HLA-Cw4 molecules in both conformations, namely, also as free heavy chains. Isoelectrofocusing analysis confirmed the presence of both HLA-Cw4 molecular conformations in activated T cells and indicated that HLA-Cw4 heavy chains can bind to mouse beta2m with the same low affinity displayed for human beta2m. The results of our experiments led us to conclude that (1) association with beta2m is not necessary for the exposure of HLA-C on the surface of activated T lymphocytes and (2) cell activation affects the balance between the two conformational forms of HLA-C.

Animals↗

PubMed1998

Pathophysiology in endothelin-1 transgenic mice.

Transgenic mice expressing the human endothelin-1 (ET-1) were generated. These mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. Consequently, a progressive decrease in renal blood flow and/or glomerular filtration rate was observed, demonstrated by altered creatinine clearance and by magnetic resonance imaging. These genetically altered transgenic mice provide an interesting animal model in which to elucidate the role of ET-1 in the modulation of renal hemodynamics and glomerular and tubule functions.

Animals↗

PubMed1997

Tumor progression and cellular differentiation of pulmonary adenocarcinomas in SV40 large T antigen transgenic mice.

Transgenic mice harboring the SV40 early region genes under transcriptional control of regulatory regions from the human surfactant protein C (SP-C) gene were used to study the progression of pulmonary adenocarcinomas in vivo. SP-C/SV40 early region gene (SP-C/TAg) transgenic mice consistently developed pulmonary adenocarcinomas. Distinct neoplasia was first detected at 4 wk of age and large tumor nodules were observed by 20-29 wk of age. SV40 large T mRNA was detected in distal bronchiolar and alveolar epithelial cells prior to tumor formation and in neoplastic cells at all stages of tumor development. SV40 large T mRNA correlated with cyclin-dependent kinase 1 (cdk1) mRNA expression, a marker of cellular proliferation. The nonciliated bronchiolar cell marker, CC10 mRNA, was detected in the majority of lung tumors at all ages, but was consistently decreased in the larger tumor nodules at later stages of tumor progression. CC10 mRNA was not detected in multiple murine lung epithelial (MLE) cell lines derived from the SP-C/TAg mice when cultured in vitro; but was induced in the MLE-15 clonal cell line when propagated in vivo in the flanks of nude mice. SP-C mRNA, an alveolar Type II cell marker, was also expressed in the MLE-15 cells when grown in nude mice. However, CC10 and SP-C mRNAs were expressed in distinct, nonoverlapping regions of the MLE-15 tumors. These studies support the concept that tumor progression is associated with changes in respiratory epithelial cell differentiation, and that the expression of bronchiolar and alveolar cell specific markers can be induced in a clonal cell line with changes in cellular environment.

Adenocarcinoma↗

PubMed2000

Mechanisms mediating the renal profibrotic actions of vasoactive peptides in transgenic mice.

Transgenic mice are useful tools to investigate the mechanisms of the renal profibrotic actions of endothelin and angiotensin II. The overexpression of angiotensinogen and renin genes induces renal sclerosis independently of changes in systemic hemodynamics. The same results are observed when the endothelin-1 gene is overexpressed. Transgenic mice harboring the luciferase gene, under the control of the collagen I alpha2 chain promoter, and made hypertensive by induction of a nitric oxide (NO) deficiency have been studied. In this strain of mice, luciferase activity is an early index of renal and vascular fibrosis. Luciferase activity was increased in preglomerular arterioles and glomeruli when mice were treated with N:(omega)-nitro-L-arginine methyl ester, an inhibitor of NO synthases. Bosentan (an endothelin receptor antagonist) was as efficient as losartan (an AT1 receptor antagonist) in preventing renal fibrosis, although it did not decrease BP. In short-term experiments, angiotensin II produced an increase in luciferase activity that was entirely prevented by losartan but also by bosentan. It can be concluded that, during chronic inhibition of NO, the collagen I gene is activated, which contributes to the development of nephroangiosclerosis and glomerulosclerosis. Angiotensin II plays a major role in this fibrogenic process, and its effect is at least partly independent of systemic hemodynamics and mediated by the profibrotic action of endothelin-1.

Animals↗

PubMed1996

Transforming growth factor-beta fails to inhibit allograft rejection or virus-induced autoimmune diabetes in transgenic mice.

Transgenic mice whose pancreata express transforming growth factor-beta (TGF-beta) directed by an insulin promoter (Ins-TGF-beta mice) were used to assess the effect of local TGF-beta1 on allograft rejection and on autoimmune diabetes occurring as a cross-reaction to viral antigens. Pancreatic TGF-beta1 did not delay allograft rejection, nor did it inhibit autoimmune diabetes after lymphocytic choriomeningitis infection of double transgenic mice (LCMV/TGF-beta1 mice). These results suggest that local TGF-beta1 does not serve as an immunosuppressive agent for allograft rejection or virus-mediated autoimmune diabetes.

Animals↗

PubMed1994

Site-specific hippocampal pathophysiology due to cerebral overexpression of interleukin-6 in transgenic mice.

Transgenic mice expressing the cytokine interleukin-6 exhibit distinctive hippocampal interneuron pathology and behavioral seizures. Electroencephalographic recordings from these mice revealed anomalous hippocampal paroxysmal discharges and suppressed theta rhythm. Analysis of hippocampal field responses evoked by monosynaptic afferent stimulation revealed a site-specific increase in recurrent inhibition in the dentate gyrus. In addition, the cholinergic component of septohippocampal conditioning of dentate-evoked activity was absent in the transgenic mice. These results indicate that overexpression of interleukin-6 selectively disrupts cholinergic transmission by inducing a functional pathophysiology of hippocampal cholinoceptive target neurons.

Animals↗

PubMed1989

Tolerance to class II MHC in transgenic mice.

Transgenic mice offer new possibilities in experimental techniques for understanding the familiar questions of T cell development and the selection of the T cell repertoire. As a powerful method to manipulate gene expression in the whole animal, precisely defined in vivo models can be developed. In our own studies, we have used transgenic mice with targeted expression of I-E and new monoclonal antibodies defining T cell receptors specific for class II I-E molecules. In the thymus, our results suggest that thymic epithelium has significant tolerance inducing capability, but the mechanism may be different from the clonal deletion induced by bone marrow derived cells. In the periphery, our results suggest that tolerance to tissue restricted antigens is not induced by clonal deletion. Instead, clonal paralysis may be an important mechanism for both inducing and maintaining peripheral tolerance.

Animals↗

PubMed1996

Specific expression in brain and liver driven by the hemopexin promoter in transgenic mice.

Transgenic mice harboring the human hemopexin promoter sequences linked to the lacZ reporter gene were generated and analyzed for temporal and spatial distribution of beta-galactosidase. Upstream sequences spanning from -1800, -700 and -500 bp to the transcription start point direct regulated beta-galactosidase expression specifically to the liver and to the brain of transgenic mice. These results suggest that the 500 bp DNA fragment flanking the 5'end of the human hemopexin gene contains the cis-acting elements required for tissue and developmental stage-specific expression in vivo and provide evidence for a new extrahepatic site of expression of the hemopexin gene.

Acute-Phase Reaction↗

PubMed1995

Evidence for in vivo non-mutagenicity of the carcinogen hydrazine sulfate in target tissues of lacZ transgenic mice.

Transgenic mouse models permit the confirmation of in vitro mutagenicity in vivo without the constraints in the selection of tissues imposed by other in vivo assays. This feature is of particular importance in the determination of mutagenicity in the target tissues of carcinogens, especially those that are in vitro mutagens. Such information is critical in the determination of whether a chemical is carcinogenic via a genotoxic or non-genotoxic mechanism. Hydrazine sulfate is an in vitro mutagen that induces lung and liver tumours in mice. Transgenic mice from strain 40.6 (Mutamouse) were administered single oral doses up to a toxic concentration (400 mg/kg). No dose induced any lacZ mutations in lung, liver or bone marrow. Since the highest single dose used is higher than the cumulative dose that induced tumours in previous studies, it may be that either hydrazine sulfate is genotoxic in target tissues in vivo only when given in multiple doses or that it is a non-genotoxic carcinogen.

Administration, Oral↗

PubMed1989

Expression of human insulin and hybrid insulin genes in pancreatic beta cells of transgenic mice.

Transgenic mice which specifically express the human insulin gene in the pancreatic beta cells were obtained by microinjection of DNA into fertilized one-cell embryos. The elements regulating in vivo the beta-cell specificity of the insulin gene, located within a few hundred base pairs upstream to the start site of transcription, were used to construct hybrid genes expressed in pancreatic beta cells. Expression of SV40-T large antigen resulted in beta-cell proliferation and beta-cell tumors, while major histocompatibility, or interferon-gamma molecules induced diabetes mellitus in transgenic mice.

Animals↗

PubMed1999

Acinar-ductal-carcinoma sequence in transforming growth factor-alpha transgenic mice.

Transgenic mice overexpressing transforming growth factor-alpha (TGF-alpha) display an expansion of intrapancreatic fibroblasts and a progressive accumulation of extracellular matrix. This massive fibrosis is associated with an increase in pancreatic size and weight. In parallel, tubular complexes appear that are composed of acinar cells with a decreased height. These acinar cell lose zymogen granules and become transitional cells, which subsequently gain duct cell features. In animals older than one year dysplastic lesions develop, which originate from tubular complexes. Occasionally these dysplastic foci transform to papillary and cystic pancreatic carcinoma. These tumors are positive for the duct-specific antigen Duct-1 and carbonic anhydrase activity indicative of ductal differentiation. Tumors overexpress the epidermal growth factor (EGF)-receptor and p53, but lack K-ras mutations. These data suggest an acinar-ductal-carcinoma sequence in TGF-alpha transgenic mice.

3T3 Cells↗

PubMed1992

5' flanking sequences of the rat tyrosine hydroxylase gene target accurate tissue-specific, developmental, and transsynaptic expression in transgenic mice.

Transgenic mice were generated in which sequences that flank the rat tyrosine hydroxylase (TH) gene were linked to the bacterial chloramphenicol acetyl transferase (CAT) gene. Mice bearing 4.8 kilobases (kb) of 5' flanking DNA exhibited correct tissue-specific expression in the CNS and periphery. Expression was more robust in the CNS than in the periphery, although CAT activity was clearly detected in sympathetic ganglia (superior cervical ganglia) and the adrenal, the two peripheral tissues that contain TH-positive cells. Within the brain, CAT expression was seen in all the expected areas containing TH-positive cell bodies, with little or no expression in other regions. In the olfactory bulb, which contains the majority of the CNS TH cells, developmental expression of CAT was quantifiable and was found to parallel the postnatal rise in endogenous TH, with both TH and CAT reaching adult levels by postnatal day 21. Since TH activity in the olfactory bulb requires afferent input, the dependence of CAT activity on transsynaptic input was also assayed in transgenic mice. Like the endogenous TH activity, CAT levels were also reduced by deafferentation, in parallel with loss in endogenous dopamine levels. While previous experiments demonstrated that shorter 5' flanking regions (2.5 kb and 3.5 kb of 5' upstream sequences of the human and mouse TH gene, respectively) failed to direct accurate tissue-specific expression, our data demonstrate that 4.8 kb of 5' flanking sequence of the rat TH gene contains sufficient regulatory information to mediate appropriate tissue-specific expression in all CNS and PNS tissues, as well as to mediate developmental and transsynaptic expression in the olfactory bulb.

Animals↗

PubMed1989

Inducible expression of an hsp68-lacZ hybrid gene in transgenic mice.

Transgenic mice have been generated that express the E. coli beta-galactosidase gene under the control of the promoter from the mouse heat-shock gene, hsp68. Sequences from -664 to +113 relative to the start of transcription of the hsp68 gene were sufficient to direct stress-induced expression of the beta-galactosidase gene in adult tail tissue and various tissues of fetal stages of development. Expression was detected in situ by staining with the chromogenic substrate, X-gal. The hybrid gene was refractory to induction in preimplantation embryos until the blastocyst stage of development, as reported for the endogenous hsp68 gene. No constitutive expression was observed by in situ staining or Northern analysis at any stage of development, even in tissues that constitutively express the endogenous hsp68 gene. We conclude that the hsp68 promoter region included in the construct contains sufficient sequence information for heat and arsenite inducibility, but it does not contain sequences controlling tissue-specific expression during development. This tightly regulated inducible promoter may provide a useful tool for short-term inducible gene expression in transgenic mice.

Animals↗

PubMed1989

Regulation of expression of a sheep metallothionein 1a-sheep growth hormone fusion gene in transgenic mice.

Transgenic mice containing a sheep metallothionein 1a-sheep growth hormone fusion gene exhibited low, tissue-specific basal levels of transgene mRNA expression, resulting in slightly elevated levels of circulating growth hormone that did not lead to a detectable increase in growth. After zinc stimulation, high levels of transgene mRNA expression were induced in a number of tissues; these levels correlated with increased levels of circulating growth hormone, resulting in growth increases of up to 1.5 times the levels of controls and unstimulated transgenic mice. After removal of the zinc stimulus, transgene expression and circulating growth hormone concentrations returned to basal levels. Additional evidence from the pattern of developmental expression of the transgene suggests that zinc is the main regulator of this promoter in mice. The demonstrated regulation and low basal level of expression of the sheep metallothionein 1a promoter make it a candidate for use in other mouse transgenic studies and for use in transgenic livestock, in which regulation of expression is essential.

Animals↗

PubMed1995

Position independent expression and developmental regulation is directed by the beta myosin heavy chain gene's 5' upstream region in transgenic mice.

Transgenic mice generated with constructs containing 5.6 kb of the beta myosin heavy chain (MyHC) gene's 5' flanking region linked to the cat reporter gene express the transgene at high levels. In all 47 lines analyzed, tissue-specific accumulation of chloramphenicol acetyltransferase was found at levels proportional to the number of integrated transgene copies. Deletion constructs containing only 0.6 kb of 5' upstream region showed position effects in transgenic mice and did not demonstrate copy number dependence although transgene expression remained muscle-specific. The 5.6 kb 5' upstream region conferred appropriate developmental control of the transgene to the cardiac compartment and directs copy number dependent and position independent expression. Lines generated with a construct in which three proximal cis-acting elements were mutated showed reduced levels of transgene expression, but all maintained their position independence and copy number dependence, suggesting the presence of distinct regulatory mechanisms.

Animals↗