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Results for “Mice, Transgenic”

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At least 55 records · Page 3Linked to original sources

PubMed2003

Early detection of PrPres in BSE-infected bovine PrP transgenic mice.

Transgenic mouse lines expressing different levels of the bovine prion protein gene (boPrP(C)) were generated. Upon infection with BSE prions, all transgenic lines tested exhibited characteristics of the bovine disease. Typical CNS spongiform degeneration was observed by histopathology and presence of PrP(res) could be detected both by Western blot and immunohistochemistry (IHC) assays, confirming for this model the absence of an interspecies barrier to BSE infection. Differences in incubation times post-inoculation depend upon the expression level of boPrP(C) and the amount of prions in the inoculum. In the absence of clinical signs, pathognomonic markers of disease could be detected as early as 150 or 196 days post-inoculation by IHC and Western blot analysis, respectively. This result indicates that prion infectivity in experimental mouse bioassays can be measured earlier by assessing immunologically the presence of PrP(res) in brains from inoculated animals. Although these transgenic mice were also susceptible to sheep scrapie prion infection, the extent of incubation times was considerably longer and PrP(res) was detected in only 70 % of inoculated mice. Interestingly, transgenic mice-propagated sheep scrapie prions displayed distinct biochemical properties when compared to both the original sheep scrapie and transgenic mouse-propagated BSE inoculum.

Animals↗

PubMed2004

TNF receptor-associated factor (TRAF) domain and Bcl-2 cooperate to induce small B cell lymphoma/chronic lymphocytic leukemia in transgenic mice.

Transgenic mice overexpressing in B lymphocytes either Bcl-2 or a TNF receptor-associated factor (TRAF)2 mutant lacking the N-terminal RING and zinc finger domains located at the N terminus of the molecule (TRAF2DN), which mimics TRAF1, developed lymphadenopathy and splenomegaly due to polyclonal B cell expansion. Remarkably, TRAF2DN/Bcl-2 double-transgenic mice contained B cell populations similar to those observed in TRAF2DN mice. However, over time, they developed severe splenomegaly and lymphadenopathy, and most animals also developed leukemia, pleural effusion, and, in some cases, ascites associated with monoclonal and oligoclonal B cell neoplasms. The life span of TRAF2DN/Bcl-2 mice was markedly reduced compared with Bcl-2 and TRAF2DN single-transgenics or wild-type littermates. The expanded B cell population of TRAF2DN/Bcl-2 double-transgenic mice was primarily comprised of small/medium-size noncycling B220(M)/IgM(H)/IgD(L)/CD21(L)/CD23(NULL)/CD11b(+)/CD5+ cells that were Bcl-6-negative, consistent with a B-1 phenotype. The cells also expressed high levels of CD54 and other adhesion molecules. In vitro, these B cells showed comparable proliferation rates to those of wild-type counterparts but exhibited markedly increased survival and were resistant to apoptosis induced by chemotherapeutic agents and glucocorticoids. Histopathologic features were consistent with mouse small B cell lymphoma progressing to leukemia with many similarities to human chronic lymphocytic leukemia. Given that many human chronic lymphocytic leukemias overexpress TRAF1 and Bcl-2, our findings suggest that cooperation between Bcl-2 and TRAF pathways contributes to the development of this type of leukemia.

Animals↗

PubMed1996

Frequent spontaneous deletions at a shuttle vector locus in transgenic mice.

Transgenic mice carrying multiple copies of a recoverable lambda phage shuttle vector (lambda supF) were constructed for the purpose of studying mutagenesis in a whole animal. Spontaneous mutations in rescued supF target genes from several different lines of transgenic mice were analyzed. One mouse line, 1139, was identified in which the frequency of spontaneous mutations was unusually high (3.15 x 10(-4)), 20-fold higher than in other transgenic mice carrying a similar number of copies of the lambda transgene (approximately 100). Over 75% of the spontaneous mutations from 1139 mice were found to be deletions, whereas mostly point mutations were recovered from the other mice. In 1139 no significant variation among adult tissues has been detected. However, embryonic tissue yielded a 3- to 4-fold lower frequency of mutations, most of which were point mutations rather than deletions. The frequency of mutations at another locus, the hypoxanthine phosphoribosyl transferase gene, was not elevated in fibroblast lines established in culture from the 1139 mice. Overall, these results suggest that the deletion mutagenesis affecting the transgene sequences in 1139 mice is a locus-specific effect occurring during growth and development. The increased mutagenesis could not be explained by the degree of methylation of the transgene sequences, since hypermethylation was seen in both 1139 mice and other mice with a low frequency of shuttle vector mutations. The integrated lambda vector DNA in 1139 mice was mapped to a single site on chromosome 7, but no mechanism for the mutagenesis was suggested by this localization. It is proposed that the lambda DNA may have either integrated into an unstable genomic site or created a newly unstable locus in the process of integration.

Animals↗

PubMed1990

Tolerance to self-antigens in transgenic mice.

Transgenic mice represent a versatile experimental approach for understanding the pathways by which the immune system regulates responsiveness to self-antigens, thereby establishing self-tolerance. The introduction of immunoglobulin and T cell receptor genes with specificity for self-antigens into the germline of mice has enabled the fate of self-reactive lymphocyte precursors to be followed in vivo. The influence of both developmentally regulated, and tissue-specific gene expression on tolerance to self-antigens has been addressed using transgenic mice expressing novel self-antigens under the transcriptional control of heterologous gene promoters. The generation of transgenic mice expressing structurally altered forms of self-antigens has allowed the role of antigen-processing in the induction of tolerance to be examined. Significantly, while these studies have confirmed the classically derived principles of immunological self-tolerance, they also point to the existence of pathways, as yet undefined, by which tolerance to self-antigens may be implemented and maintained.

Animals↗

PubMed1991

Genetic element from human surfactant protein SP-C gene confers bronchiolar-alveolar cell specificity in transgenic mice.

Transgenic mice bearing chimeric genes consisting of 5'-sequences derived from the human surfactant protein C (SP-C) gene and the bacterial chloramphenicol acetyltransferase (CAT) gene were generated. Analysis of CAT activity was utilized to demonstrate tissue-specific and developmental expression of chimeric genes containing 3.7 kb of sequences from the human SP-C gene. Lung-specific expression of the 3.7 SP-C-CAT transgene was observed in eight distinct transgenic mouse lines. Expression of the 3.7 SP-C-CAT transgene was first detected in fetal lung on day 11 of gestation and increased dramatically with advancing gestational age, reaching adult levels of activity before birth. In situ hybridization demonstrated that expression of 3.7 SP-C-CAT mRNA was confined to the distal respiratory epithelium. Antisense CAT hybridization was detected in bronchiolar and type II epithelial cells in the adult lung of the 3.7 SP-C-CAT transgenic mice. In situ hybridization of four distinct 3.7 SP-C-CAT transgenic mouse lines demonstrated bronchiolar-alveolar expression of the chimeric CAT gene, although the relative intensity of expression at each site varied within the lines studied. Glucocorticoids increased murine SP-C mRNA in fetal lung organ culture. Likewise, expression of 3.7 SP-C-CAT transgene increased during fetal lung organ or explant culture and was further enhanced by glucocorticoid in vitro. The 5'-regions of human SP-C conferred developmental, lung epithelial, and glucocorticoid-enhanced expression of bacterial CAT in transgenic mice. The increased expression of SP-C accompanying prenatal lung development and exposure to glucocorticoid is mediated, at least in part, at the transcriptional level, being influenced by cis-active elements contained within the 5'-flanking region of the human SP-C gene.

Animals↗

PubMed1994

[Leukemia in delta-GAG-MYC transgenic mice].

Transgenic mice carrying two delta-gag-myc genetic constructions were produced and kept under observation during their whole life. Nineteen out of 119 transgenic mice developed such hemopoietic diseases as lymphoid tissue hyperplasia, lymphoma, lymphosarcoma and myeloma. Lymphoid tissue hyperplasia and lymphoma generally involved multiple hyperplastic and neoplastic pathologies which were regarded, on the whole, as "malignant disease". In all cases, lymphosarcoma and myeloma were the only deadly pathologies. Lymphomas and myelomas were detected after 3-9 months, lymphosarcomas--18-29 months while lymphoid tissue hyperplasia occurred virtually throughout the entire life span--3-31 months. The study has shown that transgenic mice carrying delta-gag-myc gene in their genome can be used in the designing of special models for investigations of certain patterns of leukemia.

Animals↗

PubMed1994

Alzheimer's disease and transgenic mice.

Transgenic mice overexpressing the three major neuronal isoforms of the human amyloid precursor protein (APP), APP695, APP751, APP770 may provide an animal model for the analysis of the mechanisms and risk factors leading to amyloid deposition in Alzheimer's disease (AD) and Downs syndrome (DS). We have therefore generated transgenic mice expressing these isoforms under the control of the strong metallothionin promoter. Although we can demonstrate expression of transgenic APP in several tissues including brain, expression levels never exceeded those of the endogenous mouse APP. So far we have not been able to detect pathological changes resembling those of AD and DS. However we could demonstrate significant changes in spatial navigation tasks and motor behavior in the transgenic mice. The question remains open whether overexpression of APP is sufficient to induce Alzheimer pathology.

Alzheimer Disease↗

PubMed1994

Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice.

Transgenic mice expressing the polyomavirus (PyV) middle T oncogene in the mammary epithelium develop multifocal mammary tumors that metastasize with high frequency. The potent transforming activity of PyV middle T antigen can, in part, be attributed to its ability to associate with and to activate a number of c-Src family tyrosine kinases (c-Src, c-Yes, and Fyn). As a first step toward assessing the role of individual c-Src family tyrosine kinases in PyV middle T antigen-induced mammary tumorigenesis, we have crossed transgenic mice carrying the mouse mammary tumor virus (MMTV)/PyV middle T antigen fusion gene with mice bearing a disrupted c-src proto-oncogene. In contrast to the rapid tumor progression seen in the original MMTV/PyV middle T antigen strains, mice expressing the transgene in the absence of functional c-Src rarely developed mammary tumors. After long latency, these mice did eventually develop abnormal hyperplastic mammary tissue. This growth disturbance was correlated with elevated expression of the PyV middle T antigen and the activation of the PyV middle T antigen-associated c-Yes tyrosine kinase. However, transgenic mice expressing the PyV middle T antigen in the mammary epithelium of wild-type or Yes-deficient mice developed multifocal mammary tumors with comparable kinetics. Taken together, these findings suggest that c-Src tyrosine kinase activity is required for PyV middle T antigen-induced mammary tumorigenesis and also illustrate an in vivo genetic approach to the dissection of mitogenic signal transduction pathways.

Animals↗

PubMed1991

Tissue-specific expression of the HLA-DRA gene in transgenic mice.

Transgenic mice were produced containing a 33 kilobase (kb) DNA fragment encompassing the five exons and all the known regulatory regions of the class II HLA-DRA gene. The transgene displayed regulated expression [constitutive and interferon-gamma (IFN)-gamma induced] of the human products in most mouse tissues. The tissue distribution of the DRA transgene products more closely resembled that of their mouse homologues, the endogenous H-2 Ea products, than the wider distribution of DRA products in humans. This was evident in several tissues (endothelia of small vessels, especially those of glomerular capillaries, Kupffer cells, and epithelial cells lining the gastrointestinal tract), known to differentially express class II molecules in the two species. Thus, the wider human specific pattern of expression requires an exact cis/trans complementation which is incompletely reconstituted in transgenic mice, suggesting that human-specific cis-acting elements may have arisen during evolution to direct the expression of class II genes to those anatomical regions which usually lack them in the mouse. The only example of aberrant expression of the DRA gene in the present series of transgenic mice was in the dendritic and/or epithelial cells of the thymic cortex, which displayed greatly reduced DR alpha levels in spite of a normal expression of the endogenous E alpha molecules.

Animals↗

PubMed1991

Endogenous immunoglobulin expression in mu transgenic mice.

Transgenic mice (M54) containing a functional mu heavy chain were examined to determine the effects of the transgene on rearrangement and expression of endogenous immunoglobulin genes. Two major novel findings are presented. (i) In transgenic mice, the expressed endogenous VH repertoire in LPS-generated B cell blasts and hybridomas is skewed toward expression of JH-proximal VH families (VH7183 and Q52). (ii) There is an increase in the frequency of B cells expressing lambda light chain genes in transgenic mice. Furthermore, in Abelson-MuLV transformed pre-B cells, VH to DJH is inhibited more than the D to JH rearrangement. The results presented indicate that the transgene skews the expressed VH repertoire by inhibiting the VH to DJH rearrangement while permitting an expansion of B cells expressing limited VH and lambda light chain genes.

Animals↗

PubMed1998

Active signaling by Neu in transgenic mice.

Transgenic mice engineered to overexpress the HER-2/neu/erbB-2 protooncogene under the control of a mammary-specific promoter develop mammary tumors and are a model for human breast cancer. Signal transduction by Neu was examined in situ in the tumors of these transgenic mice. This was accomplished using the PN2A monoclonal antibody, which recognizes Neu only in the phosphorylated, and therefore actively signaling, state. Immunohistochemistry using PN2A demonstrated that Neu actively signals in the tumors of Neu transgenic mice. Expression of Neu was always accompanied by co-overexpression of the endogenous epidermal growth factor receptor. Qualitatively similar results were found in mammary tumors from mice bitransgenic for the neu and transforming growth factor-alpha genes (both driven by the mouse mammary tumor virus promoter). Early mammary lesions demonstrated distinctive patterns of Neu activation relative to expression levels. Overexpression and activation were separable both temporally and spatially. These results refine the multi-step model for the role of Neu in mammary neoplasia and establish phosphorylation-state specific antibodies as a powerful tool for investigating tumor progression.

Animals↗

PubMed1995

Rabbit whey acidic protein gene upstream region controls high-level expression of bovine growth hormone in the mammary gland of transgenic mice.

Transgenic mice were produced which secreted high levels of bGH into milk. The 6.3-kb upstream region of the rabbit whey acidic protein (rWAP) gene was linked to the structural part of the bovine growth hormone (bGH) gene, and the chimeric gene was radioimmunoassay into mouse oocytes. bGH was detected by radioimmunoassay in the milk of all resulting transgenic mice. bGH concentrations in milk varied from line to line, from 1.0-16 mg/ml. This expression was not correlated to the number of transgene copies. In all lines studied, the mammary gland was the major organ expressing bGH mRNA during lactation. bGH mRNA concentrations were barely detectable in the mammary gland of cyclic females; they increased during pregnancy. These results show that the upstream region of the rWAP gene harbors powerful regulatory elements which target high levels of bGH transgene expression to the mammary gland of lactating transgenic mice.

Animals↗

PubMed1990

Specific neuronal expression of human NGF receptors in the basal forebrain and cerebellum of transgenic mice.

Transgenic mice carrying multiple copies of the human NGF receptor gene have been generated. Using a monoclonal antibody specific for the human receptor, we have detected specific expression in cholinergic neurons in the basal forebrain and Purkinje cells in the cerebellum during the postnatal period. Expression in the PNS was exemplified by immunostaining of sympathetic and sensory neurons during an early embryonic age. Transection of the sciatic nerve in transgenic animals resulted in induction of human NGF receptors, indicating that the inserted gene can be appropriately regulated. These transgenic mice will provide an opportunity to study the elements regulating the NGF receptor. Furthermore, the ability to obtain specific expression in transgenic mice will permit directed expression of heterologous genes in discrete cells important in the cholinergic septal-hippocampal pathway and the PNS.

Animals↗

PubMed2005

Disease-related regressive alterations of forebrain cholinergic system in SOD1 mutant transgenic mice.

Transgenic mice carrying the human mutated SOD1 gene with a glycine/alanine substitution at codon 93 (G93A) are a widely used model for the fatal human disease amyotrophic lateral sclerosis (ALS). In these transgenic mice, we carried out a neurochemical study not only restricted to the primarily affected regions, the cervical and lumbar segments of the spinal cord, but also to several other brain regions. At symptomatic (110 and 125 days of age), but not at pre-symptomatic (55 days of age) stages, we found significant decreases in catalytic activity of the cholinergic enzyme, choline acetyltransferase (ChAT) in the hippocampus, olfactory cortex and fronto-parietal cortex. In parallel, we observed a decreased number of basal forebrain cholinergic neurons projecting to these areas. No alterations of the cholinergic markers were noticed in the striatum and the cerebellum. A widespread marker for GABAergic neurons, glutamate decarboxylase (GAD), was unaffected in all the areas examined. Alteration of cholinergic markers in forebrain areas was paralleled by concomitant alterations in the spinal cord and brainstem, as a consequence of progressive apoptotic elimination of cholinergic motor neuron. Gestational supplementation of choline, while able to result in long-term enhancement of cholinergic activity, did not improve transgenic mice lifespan nor counteracted cholinergic impairment in brain regions and spinal cord.

Acetylcholine↗

PubMed2000

Horizontal basal cell proliferation in the olfactory epithelium of transforming growth factor-alpha transgenic mice.

Transgenic mice in which overexpression of the transforming growth factor alpha (TGF-alpha) gene was directed by the keratin-14 promoter were used to study the regulation of cell cycle progression and proliferation in vivo in the olfactory epithelium. The level of TGF-alpha protein was 73% greater in the nasal-olfactory epithelium of the transgenic mice than in that of nontransgenic littermate controls. Increased levels of TGF-alpha protein were accompanied by a 5.8-fold selective increase in the proliferation of phenotypically characterized horizontal basal cells in the transgenics compared with nontransgenics; in contrast, globose basal cells exhibited a similar low level of proliferation in both transgenics and nontransgenics. The level of expression of epidermal growth factor receptor protein, the receptor for TGF-alpha, was also upregulated in the transgenics, indicating a role for the ErbB tyrosine kinase receptor family in the response to TGF-alpha in the olfactory epithelium. TGF-alpha overexpression was also associated with increased expression of several early cell-cycle-associated proteins, including the growth factor sensor cyclin D1, retinoblastoma, E2F-1 transcription factor, and cyclin E, indicating the progression of relatively quiescent progenitor cells in the G1 phase of the cell cycle toward the G1/S restriction point, after which the cells become refractive to mitogens. These results demonstrate a role for the growth factor TGF-alpha in the in vivo regulation of cell cycle progression and proliferation in the mitotically active olfactory epithelium in these transgenic mice.

Animals↗

PubMed1997

Hepatitis C virus core and E2 protein expression in transgenic mice.

Transgenic mice have been produced that express the hepatitis C virus (HCV) core protein in the liver under the transcriptional control of the mouse major urinary protein promoter. These animals express the full length core protein in cytoplasm of their hepatocytes at levels comparable to those detected in naturally infected patients, without histological or biochemical evidence of liver disease or hepatocellular carcinoma. This contrasts with recent reports that HCV core protein can transform NIH 3T3 cells and cooperates with H-ras to transform primary rat fibroblasts in vitro. Coexpression of HCV core protein in double transgenic mice that replicate the hepatitis B virus (HBV) does not inhibit hepatocellular HBV gene expression or replication, contrary to reports that it inhibits HBV replication in HuH-7 cells after transient transfection in vitro. We have also produced transgenic mice in which a C-terminally truncated (aa384-715) glycosylated HCV E2 protein is expressed in the liver under the transcriptional control of the mouse albumin promoter. Despite the high level expression of HCV E2 protein, no evidence of liver disease was detected in these animals. These results suggest that the HCV core and E2 proteins are not cytopathic for the hepatocyte in vivo, and they represent an initial step in the development of a small animal model of HCV immunopathology.

Animals↗

PubMed1994

Analysis of viral-host protein interactions and tumorigenesis in transgenic mice.

Transgenic mice provide a valuable system with which to explore mechanisms that regulate cell growth and differentiation. The ability to target the expression of test genes to specific cell types and developmental stages facilitates the rigorous assessment of regulatory pathways operative in each cell type in vivo. The natural induction of neoplasia clearly involves multiple genetic events which include alterations both in cellular protooncogenes (dominant events) and in tumor suppressor genes (recessive events). Transgenic mice have long been used to explore the mechanism of dominant oncogene action, and continue to provide an avenue for experimentation. Recent developments in the study of DNA tumor virus oncoproteins suggest their usefulness in probing the function of certain tumor suppressors. The transforming proteins from three DNA tumor viruses, adenovirus, simian virus 40, and human papillomaviruses 16 and 18, interact with a common subset of cellular proteins to disrupt normal cellular growth regulation. The discovery that two of these proteins, pRB and p53, are tumor suppressors not only emphasizes the importance of these cellular proteins in growth regulatory processes, but also provides an approach to understanding the function of these cellular targets in vivo. Analysis of the DNA virus oncoproteins in transgenic mice has recently begun to yield insight into the role of these tumor suppressors and other cellular functions in development and tumorigenesis of a variety of cell types. This approach and recent findings which it has yielded are reviewed here.

Animals↗

PubMed1993

Cis effect of lacZ sequences in transgenic mice.

Transgenic mice carrying the 3-hydroxy-3-methylglutarylCoA reductase (HMG) promoter driving the Escherichia coli beta-galactosidase (lacZ) gene did not display the expected ubiquitous and constitutive expression in HMG-lacZ transgenic mice. The same promoter is however able to drive ubiquitous expression of the chloramphenicol acetyltransferase (cat) gene. Two lines of double HMG-lacZ and HMG-cat transgenic mice were obtained in which the two constructs were integrated at the same genomic sites. These mice expressed both reporter genes, but exclusively in the testes. These results suggest that the lacZ sequence might interfere negatively with the expression of the adjacent HMG-cat transgene.

Animals↗