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Ju Kim, H., K. i. Naruse, W. S. Choi, K. S. Im, C. S. Park und D. I. Jin. „332 ENHANCEMENT OF GROWTH PERFORMANCE IN DOUBLE TRANSGENIC MICE WITH GROWTH HORMONE RECEPTOR AND IGF-1 RECEPTOR GENES“. Reproduction, Fertility and Development 17, Nr. 2 (2005): 317. http://dx.doi.org/10.1071/rdv17n2ab332.
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The effect of amplifying growth-related receptor signaling, through overexpression of receptors, on growth regulation in animals was examined. Transgenic mice lines were produced by DNA microinjection using the metallothionein promoter ligated to either the growth hormone receptor (GHR) or IGF-1 receptor (IGF-1R) genes (3 GHR founders and 3 IGF-1R founders). Transgenic mouse lines were estimated to contain approximately 4 to 20 copies of transgenes per cell by Southern blot analysis. Founder mice of each transgenic line transmitted transgenes into F1 and F2 pups with Mendelian ratio. Double transgenic (IGF-1R/GHR) mice were produced by the mating between nine pairs of IGF-1R and GHR hemizygous transgenic F1 mice. The transmission patterns in the 78 F2 pups produced from these matings were 20 with no transgene (25.6%), 17 with the IGF-1R gene (21.8%), 25 with the GHR gene (32.1%), and 16 with both GHR and IGF-1R genes (20.5%). The mRNA expression of transgenes using RT-PCR with the specific primers for IGF-IR and GHR genes was checked in tissues of transgenic mice. Double transgenic mice with IGF-IR and GHR genes expressed more mRNAs of transgenes than non-transgenic or single transgenic mice. Growth of double transgenic mice was fastest compared with single transgenic mice containing IGF-1R or GHR genes. And GHR transgenic mice grew faster than IGF-1R transgenic mice. When body weights of 15 transgenic mice for each transgenic line were measured at 4, 10, and 14 weeks after birth, double transgenic mice were significantly heavier compared with non-transgenic control mice at each stage (24 to 30% heavier in double transgenic mice; 15 to 20% heavier in single transgenic mice, P < 0.05). These results suggest that overexpression of growth-related receptor genes could promote the growth of transgenic animals with an additive effect.
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Auerbach, Anna B. „Production of functional transgenic mice by DNA pronuclear microinjection.“ Acta Biochimica Polonica 51, Nr. 1 (31.03.2004): 9–31. http://dx.doi.org/10.18388/abp.2004_3593.
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Successful experiments involving the production of transgenic mice by pronuclear microinjection are currently limited by low efficiency of random transgene integration into the mouse genome. Furthermore, not all transgenic mice express integrated transgenes, or in other words are effective as functional transgenic mice expressing the desired product of the transgene, thus allowing accomplishment of the ultimate experimental goal--in vivo analysis of the function of the gene or gene network. The purpose of this review is to look at the current state of transgenic technology, utilizing a pronuclear microinjection method as the most accepted way of gene transfer into the mouse genome.
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Sigmund, C. D., C. A. Jones, H. J. Jacob, J. Ingelfinger, U. Kim, D. Gamble, V. J. Dzau und K. W. Gross. „Pathophysiology of vascular smooth muscle in renin promoter-T-antigen transgenic mice“. American Journal of Physiology-Renal Physiology 260, Nr. 2 (01.02.1991): F249—F257. http://dx.doi.org/10.1152/ajprenal.1991.260.2.f249.
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The pathophysiological consequence of targeted production of SV-40 T-antigen to renin-expressing cells in the kidney of transgenic mice is reported. A histopathologic analysis of the kidney from adult transgenic mice (12–16 wk old) revealed the presence of severe vascular lesions manifested by marked atypical hyperplasia of vascular smooth muscle. The levels of plasma renin, kidney renin, and kidney renin mRNA were examined in 6- and 9-wk-old transgenic mice and were found to be significantly lower than their age-matched non-transgenic littermates and were nonresponsive to captopril treatment. However, there was no significant difference in conscious mean arterial pressure between transgenic and non-transgenic mice. The levels of renal renin mRNA in transgenics and nontransgenic littermates were compared throughout ontogeny and were found to be equal in newborns, elevated 3- to 5-fold in 1-wk-old transgenics, and yet decreased 10-fold by 6 wk of age in transgenic mice. Expression of the transgene in the kidney exhibited the proper developmental pattern and was properly restricted to juxtaglomerular cells in neonatal mice. Nevertheless, in adult mice, T-antigen-containing cells were found throughout the entire renal arterial tree. The observed ability of renal vascular cells to be recruited to express both renin and T-antigen suggests a mechanism that can explain the development of the renal pathology in these mice.
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Dent, L. A., M. Strath, A. L. Mellor und C. J. Sanderson. „Eosinophilia in transgenic mice expressing interleukin 5.“ Journal of Experimental Medicine 172, Nr. 5 (01.11.1990): 1425–31. http://dx.doi.org/10.1084/jem.172.5.1425.
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Experiments in vitro suggest that although interleukin 5 (IL-5) stimulates the late stages of eosinophil differentiation, other cytokines are required for the generation of eosinophil progenitor cells. In this study transgenic mice constitutively expressing the IL-5 gene were established using a genomic fragment of the IL-5 gene coupled to the dominant control region from the gene encoding human CD2. Four independent eosinophilic transgenic lines have thus far been established, two of which with 8 and 49 transgene copies, are described in detail. These mice appeared macroscopically normal apart from splenomegaly. Eosinophils were at least 65- and 265-fold higher in blood from transgenics, relative to normal littermates, and approximately two- or sevenfold more numerous relative to blood from mice infected with the helminth Mesocestoides corti. Much more modest increases in blood neutrophil, lymphocyte, and monocyte numbers were noted in transgenics, relative to normal littermates (less than threefold). Thus IL-5 in vivo is relatively specific for the eosinophil lineage. Large numbers of eosinophils were present in spleen, bone marrow, and peritoneal exudate, and were highest in the line with the greatest transgene copy number. Eosinophilia was also noted in histological sections of transgenic lungs, Peyer's patches, mesenteric lymph nodes, and gut lamina propria but not in other tissues examined. IL-5 was detected in the sera of transgenics at levels comparable to those seen in sera from parasite-infected animals. IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF) were not found. IL-5 mRNA was detected in transgenic thymus, Peyer's patches, and superficial lymph nodes, but not in heart, liver, brain, or skeletal muscle or in any tissues from nontransgenics. Bone marrow from transgenic mice was rich in IL-5-dependent eosinophil precursors. These data indicate that induction of the IL-5 gene is sufficient for production of eosinophilia, and that IL-5 can induce the full pathway of eosinophil differentiation. IL-5 may therefore not be restricted in action to the later stages of eosinophil differentiation, as suggested by earlier in vitro studies.
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Kong, Siyuan, Jinxue Ruan, Kaiyi Zhang, Bingjun Hu, Yuzhu Cheng, Yubo Zhang, Shulin Yang und Kui Li. „Kill two birds with one stone: making multi-transgenic pre-diabetes mouse models through insulin resistance and pancreatic apoptosis pathogenesis“. PeerJ 6 (17.04.2018): e4542. http://dx.doi.org/10.7717/peerj.4542.
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Background Type 2 diabetes is characterized by insulin resistance accompanied by defective insulin secretion. Transgenic mouse models play an important role in medical research. However, single transgenic mouse models may not mimic the complex phenotypes of most cases of type 2 diabetes. Methods Focusing on genes related to pancreatic islet damage, peripheral insulin resistance and related environmental inducing factors, we generated single-transgenic (C/EBP homology protein, CHOP) mice (CHOP mice), dual-transgenic (human islet amyloid polypeptide, hIAPP; CHOP) mice (hIAPP-CHOP mice) and triple-transgenic (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1; hIAPP; CHOP) mice (11β-HSD1-hIAPP- CHOP mice). The latter two types of transgenic (Tg) animals were induced with high-fat high-sucrose diets (HFHSD). We analyzed the diabetes-related symptoms and histology features of the transgenic animals. Results Comparing symptoms on the spot-checked points, we determined that the triple-transgene mice were more suitable for systematic study. The results of intraperitoneal glucose tolerance tests (IPGTT) of triple-transgene animals began to change 60 days after induction (p < 0.001). After 190 days of induction, the body weights (p < 0.01) and plasma glucose of the animals in Tg were higher than those of the animals in Negative Control (Nc). After sacrificed, large amounts of lipid were found deposited in adipose (p < 0.01) and ectopically deposited in the non-adipose tissues (p < 0.05 or 0.01) of the animals in the Tg HFHSD group. The weights of kidneys and hearts of Tg animals were significantly increased (p < 0.01). Serum C peptide (C-P) was decreased due to Tg effects, and insulin levels were increased due to the effects of the HFHSD in the Tg HFHSD group, indicating that damaged insulin secretion and insulin resistance hyperinsulinemia existed simultaneously in these animals. The serum corticosterone of Tg was slightly higher than those of Nc due to the effects of the 11βHSD-1 transgene and obesity. In Tg HFHSD, hepatic adipose deposition was more severe and the pancreatic islet area was enlarged under compensation, accompanying apoptosis. In the transgenic control diet (Tg ControlD) group, hepatic adipose deposition was also severe, pancreatic islets were damaged, and their areas were decreased (p < 0.05), and apoptosis of pancreatic cells occurred. Taken together, these data show the transgenes led to early-stage pathological changes characteristic of type 2 diabetes in the triple-transgene HFHSD group. The disease of triple-transgenic mice was more severe than that of dual or single-transgenic mice. Conclusion The use of multi-transgenes involved in insulin resistance and pancreatic apoptosis is a better way to generate polygene-related early-stage diabetes models.
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Choi, T., M. Huang, C. Gorman und R. Jaenisch. „A generic intron increases gene expression in transgenic mice“. Molecular and Cellular Biology 11, Nr. 6 (Juni 1991): 3070–74. http://dx.doi.org/10.1128/mcb.11.6.3070-3074.1991.
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To investigate the role of splicing in the regulation of gene expression, we have generated transgenic mice carrying the human histone H4 promoter linked to the bacterial gene for chloramphenicol acetyltransferase (CAT), with or without a heterologous intron in the transcription unit. We found that CAT activity is 5- to 300-fold higher when the transgene incorporates a hybrid intron than with an analogous transgene precisely deleted for the intervening sequences. This hybrid intron, consisting of an adenovirus splice donor and an immunoglobulin G splice acceptor, stimulated expression in a broad range of tissues in the animal. Although the presence of the hybrid intron increased the frequency of transgenics with significant CAT activity, it did not affect the integration site-dependent variation commonly seen in transgene expression. To determine whether the enhancement is a general outcome of splicing or is dependent on the particular intron, we also produced equivalent transgenics carrying the widely used simian virus 40 small-t intron. We found that the hybrid intron is significantly more effective in elevating transgene expression. Our results suggest that inclusion of the generic intron in cDNA constructs may be valuable in achieving high levels of expression in transgenic mice.
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Choi, T., M. Huang, C. Gorman und R. Jaenisch. „A generic intron increases gene expression in transgenic mice.“ Molecular and Cellular Biology 11, Nr. 6 (Juni 1991): 3070–74. http://dx.doi.org/10.1128/mcb.11.6.3070.
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To investigate the role of splicing in the regulation of gene expression, we have generated transgenic mice carrying the human histone H4 promoter linked to the bacterial gene for chloramphenicol acetyltransferase (CAT), with or without a heterologous intron in the transcription unit. We found that CAT activity is 5- to 300-fold higher when the transgene incorporates a hybrid intron than with an analogous transgene precisely deleted for the intervening sequences. This hybrid intron, consisting of an adenovirus splice donor and an immunoglobulin G splice acceptor, stimulated expression in a broad range of tissues in the animal. Although the presence of the hybrid intron increased the frequency of transgenics with significant CAT activity, it did not affect the integration site-dependent variation commonly seen in transgene expression. To determine whether the enhancement is a general outcome of splicing or is dependent on the particular intron, we also produced equivalent transgenics carrying the widely used simian virus 40 small-t intron. We found that the hybrid intron is significantly more effective in elevating transgene expression. Our results suggest that inclusion of the generic intron in cDNA constructs may be valuable in achieving high levels of expression in transgenic mice.
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Heinzelmann, Andy, Subbiah Kumar, Scott Noggle, Ine Goedegebuur, K. Morgan Sauer, Satyajit Rath und Jeannine M. Durdik. „Deletion of a Recombined Ig Heavy Chain Transgene in B-Lineage Cells of Transgenic Mice“. Journal of Immunology 161, Nr. 2 (15.07.1998): 666–73. http://dx.doi.org/10.4049/jimmunol.161.2.666.
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Abstract Fully recombined transgenes are stable in their transmission in the germline of transgenic mice, in common with the endogenous genetic complement of most mammalian somatic tissues, including the genes for lymphoid Ag receptors somatically generated from germline minigenes. There have, however, been isolated reports of unusual low frequency transgene losses in various transgenic mice. Here we show, using Southern blots and PCR-based assays, that plasmablast hybridomas and B cells from three independently derived founder lines of transgenic mice bearing a recombined heavy chain Ig transgene we have been studying show a significant net loss of transgene copies. This loss is more marked in the B cells expressing endogenous heavy chains than in those expressing transgenic heavy chains. We have also examined cells of the B lineage in the bone marrow, and a small degree of deletion is also evident in CD19+CD23−IgM− immature B-lineage cells. As greater deletion is observed in mature B cells, it is possible that the deletion process either continues into B cell maturity and/or provides a selective advantage. We have investigated the relationship between transgene expression and deletion, and we find that while thymocytes in these mice express the transgene well, T cell hybridomas derived from transgenic thymus do not show any loss of the transgene. Thus, a recombined Ig heavy chain transgene prominently undergoes somatic deletion in B-lineage cells independent of its insertion site or expression. This transgenic instability is significant to the analysis of genomic stability as well as to the design of gene therapy strategies.
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Xing, Shu, Wanming Zhao, Wanting Tina Ho und Zhizhuang Joe Zhao. „Transgenic Expression of Wild Type JAK2 Suppresses Myeloproliferative Disorder Phenotypes Induced by Mutant JAK2V617F in Mice“. Blood 112, Nr. 11 (16.11.2008): 180. http://dx.doi.org/10.1182/blood.v112.11.180.180.
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Abstract JAK2V617F, a mutant form of tyrosine kinase JAK2, is found in the majority of patients with myeloproliferative disorders (MPDs). It displays increased kinase activity and causes MPD phenotypes in transgenic mice in a transgence dosage-dependent manner. Following our initial generation and characterization of JAK2V617F transgenic mice, we further generated transgenic mice expressing wild type JAK2 by using the same vav promoter employed for JAK2V617F. Three lines of JAK2 transgenic mice were generated. Real time PCR analyses revealed transgene copy numbers of 38, 2, and 1. All these mice are viable and fertile, and they displayed normal blood cell counts. This proves that the V617F mutation but not gene overexpression per se caused MPD phenotypes in JAK2V617F transgenic mice. We then crossed the JAK2 and JAK2V617F transgenic mice to generate JAK2/JAK2V617F double transgenic hybrids. Interestingly, these hybrid mice developed no or mild MPD phenotypes with only a slight increase in blood counts in contrast to the striking elevation observed in JAK2V617F transgenic mice. Expression of wild type JAK2 also blocked the constitutive activation of signal transduction components caused by JAK2V617F. Our data indicates that over-expression of wild type JAK2 suppresses the pathogenic function of mutant JAK2V617F. Therefore, JAK2V617F is not a typical dominant oncogene. Homozygous mutation or in the case of heterozygous mutation, its amplification with concurrent deletion or suppression of wild type JAK2, is required to produce MPD phenotypes. Our transgenic mouse models will serve as an invaluable tool to study the interplay of JAK2 and JAK2V617F and the mechanism by which specific MPD phenotypes develop.
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Picarella, D. E., A. Kratz, C. B. Li, N. H. Ruddle und R. A. Flavell. „Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice.“ Journal of Immunology 150, Nr. 9 (01.05.1993): 4136–50. http://dx.doi.org/10.4049/jimmunol.150.9.4136.
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Abstract To understand the role of TNF in the regulation of inflammation and the development of autoimmune diseases such as insulin-dependent diabetes mellitus, we produced transgenic mice in which the synthesis of murine TNF-alpha was directed by the rat insulin II promoter. The expression of the TNF-alpha transgene was restricted to the pancreas, in contrast to TNF-beta expression from the same promoter, in which the transgene was expressed in the pancreas, kidney, and skin. The expression of TNF-alpha in the pancreas of transgenic mice resulted in an overwhelming insulitis, composed of CD4+ and CD8+ T cells and B220+ B cells, considerably greater than that of TNF-beta transgenics. Moreover, in contrast to the predominant peri-insulitis observed in TNF-beta transgenic mice, the majority of the infiltrate in the TNF-alpha transgenic mice was within the islet itself. These unique patterns of infiltration were observed in the F1 progeny of crosses with C57BL/6 as well as NOD. Both TNF-alpha and TNF-beta transgenic mice show elevated expression of leukocyte adhesion molecules VCAM-1 and ICAM-1 in islet endothelia and increased expression of MHC class I on islet cells. This inflammation did not result in reduced insulin content of the islets, nor did it lead to diabetes. These data suggest that additional stimuli are necessary to initiate the process of islet destruction.
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Babinet, C., D. Morello und J. P. Renard. „Transgenic mice“. Genome 31, Nr. 2 (15.01.1989): 938–49. http://dx.doi.org/10.1139/g89-165.
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Stable integration into the mouse genome of exogenous genetic information has become, over the past few years, a very potent approach for different aspects of biology. It is a common feature that the integrated exogenous gene (the transgene) is expressed properly both spatially and temporally. Constructing different lines of transgenic mice carrying various versions of a gene, therefore, permits cis acting DNA sequences involved in the specificity of expression to be defined, in the context of the developing animal. This in turn opens the way to a variety of experiments in which a given gene product is targeted to one or another cell type, thus offering some insight into the physiological role of this product. Such a strategy has been used, for example, to address the questions of the role of oncogenes in malignant transformation. The insertion of foreign DNA per se may disrupt the function of endogenous genes, thus creating an insertional mutation. The corresponding affected genes may subsequently be cloned, using the transgene as a tag. Finally, the ability to perform homologous recombination, recently demonstrated with embryonic stem cells that can colonize the germ line of a foreign embryo, should constitute in the near future a unique way to analyse in detail the functioning of the mammalian genome.Key words: transgenic mice, oncogenes, insertional mutagenesis, cis-acting sequences, homologous recombination.
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Wei, S., Y. Feng, FY Che, H. Pan, N. Mzhavia, LA Devi, AA McKinzie, N. Levin, WG Richards und LD Fricker. „Obesity and diabetes in transgenic mice expressing proSAAS“. Journal of Endocrinology 180, Nr. 3 (01.03.2004): 357–68. http://dx.doi.org/10.1677/joe.0.1800357.
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ProSAAS is a neuroendocrine peptide precursor that potently inhibits prohormone convertase 1 in vitro. To explore the function of proSAAS and its derived peptides, transgenic mice were created which express proSAAS using the beta-actin promoter. The body weight of transgenic mice was normal until approximately 10-12 weeks, and then increased 30-50% over wild-type littermates. Adult transgenic mice had a fat mass approximately twice that of wild-type mice, and fasting blood glucose levels were slightly elevated. In the pituitary, the levels of several fully processed peptides in transgenic mice were not reduced compared with wild-type mice, indicating that the proSAAS transgene did not affect prohormone convertase 1 activity in this tissue. Because the inhibitory potency of proSAAS-derived peptides towards prohormone convertase 1 is much greater in the absence of carboxypeptidase E activity, the proSAAS transgene was also expressed in carboxypeptidase E-deficient Cpe (fat/fat) mice. Although the transgenic mice were born in the expected frequency, 21 of 22 proSAAS transgenic Cpe (fat/fat) mice died between 11 and 26 weeks of age, presumably due to greatly elevated blood glucose. The levels of several pituitary peptides were significantly reduced in the proSAAS transgenic Cpe (fat/fat) mice relative to non-transgenic Cpe (fat/fat) mice, suggesting that the transgene inhibited prohormone convertase 1 in these mice. Taken together, these results are consistent with a role for proSAAS-derived peptides as neuropeptides that influence body weight independently of their function as inhibitors of prohormone convertase 1.
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Storb, U., C. Pinkert, B. Arp, P. Engler, K. Gollahon, J. Manz, W. Brady und R. L. Brinster. „Transgenic mice with mu and kappa genes encoding antiphosphorylcholine antibodies.“ Journal of Experimental Medicine 164, Nr. 2 (01.08.1986): 627–41. http://dx.doi.org/10.1084/jem.164.2.627.
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Transgenic mice were produced that carried in their germlines rearranged kappa and/or mu genes with V kappa and VH regions from the myeloma MOPC-167 kappa and H genes, which encode anti-PC antibody. The mu genes contain either a complete gene, including the membrane terminus (mu genes), or genes in which this terminus is deleted and only the secreted terminus remains (mu delta mem genes). The mu gene without membrane terminus is expressed at as high a level as the mu gene with the complete 3' end, suggesting that this terminus is not required for chromatin activation of the mu locus or for stability of the mRNA. The transgenes are expressed only in lymphoid organs. In contrast to our previous studies with MOPC-21 kappa transgenic mice, the mu transgene is transcribed in T lymphocytes as well as B lymphocytes. Thymocytes from mu and kappa mu transgenic mice display elevated levels of M-167 mu RNA and do not show elevated levels of kappa RNA, even though higher than normal levels of M-167 kappa RNA are detected in the spleen of these mice. Approximately 60% of thymocytes of mu transgenic mice produce cytoplasmic mu protein. However, despite a large amount of mu RNA of the membrane form, mu protein cannot be detected on the surface of T cells, perhaps because it cannot associate with T cell receptor alpha or beta chains. Mice with the complete mu transgene produce not only the mu transgenic mRNA but also considerably increased amounts of kappa RNA encoded by endogenous MOPC-167 like kappa genes. This suggests that B cells are selected by antigen (PC) if they coexpress the mu transgene and appropriate anti-PC endogenous kappa genes. Mice with the mu delta mem gene, however, do not express detectable levels of the endogenous MOPC-167 kappa mRNA. Like the complete mu transgene, the M-167 kappa transgene also causes amplification of endogenous MOPC-167 related immunoglobulins; mice with the kappa transgene have increased amounts of endogenous MOPC-167-like mu or alpha or gamma in the spleen, all of the secreted form. Implications for the regulation of immunoglobulin gene expression and B cell triggering are discussed.
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Kwan, H., V. Pecenka, A. Tsukamoto, T. G. Parslow, R. Guzman, T. P. Lin, W. J. Muller, F. S. Lee, P. Leder und H. E. Varmus. „Transgenes expressing the Wnt-1 and int-2 proto-oncogenes cooperate during mammary carcinogenesis in doubly transgenic mice“. Molecular and Cellular Biology 12, Nr. 1 (Januar 1992): 147–54. http://dx.doi.org/10.1128/mcb.12.1.147-154.1992.
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The Wnt-1 and int-2 proto-oncogenes are transcriptionally activated by mouse mammary tumor virus insertion mutations in virus-induced tumors and encode secretory glycoproteins. To determine whether these two genes can cooperate during carcinogenesis, we have crossed two previously characterized lines of transgenic mice to obtain bitransgenic animals carrying both Wnt-1 and int-2 transgenes under the control of the mouse mammary tumor virus long terminal repeat. Mammary carcinomas appear earlier and with higher frequency in the bitransgenic animals, especially the males, than in either parental line. Nearly all bitransgenic males develop mammary neoplasms within 8 months of birth, whereas only 15% of Wnt-1 transgenic males and none of the int-2 transgenic males have tumors. In virgin bitransgenic females, tumors occur approximately 2 months earlier than in their Wnt-1 transgenic siblings; int-2 transgenic females rarely exhibit tumors. Preneoplastic glands from the bitransgenic animals of either sex demonstrate pronounced epithelial hyperplasia similar to that seen in Wnt-1 transgenic virgin females and males, and both transgenes are expressed in the hyperplastic glands and mammary tumors. RNA from the int-2 transgene is more abundant in mammary glands from bitransgenic animals than from int-2 transgenic animals; the increase is associated with high levels of RNA specific for keratin genes 14 and 18, suggesting that Wnt-1-induced epithelial hyperplasia is responsible for the observed increase in expression of the int-2 transgene.
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Kwan, H., V. Pecenka, A. Tsukamoto, T. G. Parslow, R. Guzman, T. P. Lin, W. J. Muller, F. S. Lee, P. Leder und H. E. Varmus. „Transgenes expressing the Wnt-1 and int-2 proto-oncogenes cooperate during mammary carcinogenesis in doubly transgenic mice.“ Molecular and Cellular Biology 12, Nr. 1 (Januar 1992): 147–54. http://dx.doi.org/10.1128/mcb.12.1.147.
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The Wnt-1 and int-2 proto-oncogenes are transcriptionally activated by mouse mammary tumor virus insertion mutations in virus-induced tumors and encode secretory glycoproteins. To determine whether these two genes can cooperate during carcinogenesis, we have crossed two previously characterized lines of transgenic mice to obtain bitransgenic animals carrying both Wnt-1 and int-2 transgenes under the control of the mouse mammary tumor virus long terminal repeat. Mammary carcinomas appear earlier and with higher frequency in the bitransgenic animals, especially the males, than in either parental line. Nearly all bitransgenic males develop mammary neoplasms within 8 months of birth, whereas only 15% of Wnt-1 transgenic males and none of the int-2 transgenic males have tumors. In virgin bitransgenic females, tumors occur approximately 2 months earlier than in their Wnt-1 transgenic siblings; int-2 transgenic females rarely exhibit tumors. Preneoplastic glands from the bitransgenic animals of either sex demonstrate pronounced epithelial hyperplasia similar to that seen in Wnt-1 transgenic virgin females and males, and both transgenes are expressed in the hyperplastic glands and mammary tumors. RNA from the int-2 transgene is more abundant in mammary glands from bitransgenic animals than from int-2 transgenic animals; the increase is associated with high levels of RNA specific for keratin genes 14 and 18, suggesting that Wnt-1-induced epithelial hyperplasia is responsible for the observed increase in expression of the int-2 transgene.
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Kolb, Andreas F., Lecia Pewe, John Webster, Stanley Perlman, C. Bruce A. Whitelaw und Stuart G. Siddell. „Virus-Neutralizing Monoclonal Antibody Expressed in Milk of Transgenic Mice Provides Full Protection against Virus-Induced Encephalitis“. Journal of Virology 75, Nr. 6 (15.03.2001): 2803–9. http://dx.doi.org/10.1128/jvi.75.6.2803-2809.2001.
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ABSTRACT Neutralizing antibodies represent a major host defense mechanism against viral infections. In mammals, passive immunity is provided by neutralizing antibodies passed to the offspring via the placenta or the milk as immunoglobulin G and secreted immunoglobulin A. With the long-term goal of producing virus-resistant livestock, we have generated mice carrying transgenes that encode the light and heavy chains of an antibody that is able to neutralize the neurotropic JHM strain of murine hepatitis virus (MHV-JHM). MHV-JHM causes acute encephalitis and acute and chronic demyelination in susceptible strains of mice and rats. Transgene expression was targeted to the lactating mammary gland by using the ovine β-lactoglobulin promoter. Milk from these transgenic mice contained up to 0.7 mg of recombinant antibody/ml. In vitro analysis of milk derived from different transgenic lines revealed a linear correlation between antibody expression and virus-neutralizing activity, indicating that the recombinant antibody is the major determinant of MHV-JHM neutralization in murine milk. Offspring of transgenic and control mice were challenged with a lethal dose of MHV-JHM. Litters suckling nontransgenic dams succumbed to fatal encephalitis, whereas litters suckling transgenic dams were fully protected against challenge, irrespective of whether they were transgenic. This demonstrates that a single neutralizing antibody expressed in the milk of transgenic mice is sufficient to completely protect suckling offspring against MHV-JHM-induced encephalitis.
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Sigurdardottir, D., J. Sohn, J. Kass und E. Selsing. „Regulatory regions 3' of the immunoglobulin heavy chain intronic enhancer differentially affect expression of a heavy chain transgene in resting and activated B cells.“ Journal of Immunology 154, Nr. 5 (01.03.1995): 2217–25. http://dx.doi.org/10.4049/jimmunol.154.5.2217.
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Abstract We have compared the expression patterns of three Ig heavy chain transgenes. The three constructs differ only by deletion of J-C intron sequences located downstream of the Emu enhancer region. When stably transfected into a myeloma cell line, all three constructs are expressed at comparable levels. However, transgenic mice carrying each construct show dramatic differences in transgene expression. Our results indicate that, in addition to the Emu enhancer, at least two regions, RegA and RegS, within the J-C intron influence transgene expression. RegA, located directly downstream of the core Emu enhancer, is involved in up-regulation of transgene expression after LPS activation of splenocytes. RegS, located within or downstream of the Smu switch region, is important for normal levels of transgene expression in splenocytes of heavy chain transgenic mice.
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Painter, Meghan, und Moses Rodriguez. „Intrinsic upregulation of critical innate immune effectors in a novel transgenic mouse model confers viral resistance (P1389)“. Journal of Immunology 190, Nr. 1_Supplement (01.05.2013): 57.6. http://dx.doi.org/10.4049/jimmunol.190.supp.57.6.
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Abstract Our laboratory generated a transgenic mouse that ubiquitously expresses 3D, a picorno viral RNA-dependent RNA polymerase. 3D transgenic mice display an extreme antiviral phenotype when challenged with viruses from distinct families. To probe this protective molecular mechanism, we assayed differential gene expression in tissues of uninfected 3D transgenic mice. Microarray analysis revealed increased levels of 78 genes >4-fold, including a distinct upregulation of critical innate antiviral effectors across tissues. RT-PCR analysis of liver, lung, kidney, CNS and heart tissue from uninfected 3D mice showed a significant upregulation of antiviral genes (up to 300-fold). Following infection with EMCV, 3D transgenic mice exhibited significantly decreased viral tissue titers and survived lethal viral infection. This effect is specific to the 3D transgene since other mice expressing the picorno viral transgenes VP1 or VP2 did not display an antiviral phenotype. Studies of 3D-Ifnar1-/- or 3D-Ifngr1-/- mice, supported the conclusion that type I IFN signaling is necessary for the antiviral state in 3D mice, whereas IFNg signaling is dispensable. Maintenance of a viral-resistant state in uninfected 3D mice is independent of adaptive immunity since uninfected 3D-Rag1-/- mice are able to highly upregulate antiviral factors. Collectively, our data indicate that intrinsic upregulation of critical innate immune effectors confers broad-spectrum viral resistance in 3D mice.
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Plopper, C. G., C. Helton, A. J. Weir, J. A. Whitsett und T. R. Korfhagen. „Quantitative Microscopic Comparison of the Organization of the Lung in Transgenic Mice Expressing Transforming Growth Factor-α (TGF-α)“. Proceedings, annual meeting, Electron Microscopy Society of America 54 (11.08.1996): 14–15. http://dx.doi.org/10.1017/s0424820100162533.
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A wide variety of growth factors are thought to be involved in the regulation of pre- and postnatal lung maturation, including factors which bind to the epidermal growth factor receptor. Marked pulmonary fibrosis and enlarged alveolar air spaces have been observed in lungs of transgenic mice expressing human TGF-α under control of the 3.7 KB human SP-C promoter. To test whether TGF-α alters lung morphogenesis and cellular differentiation, we examined morphometrically the lungs of adult (6-10 months) mice derived from line 28, which expresses the highest level of human TGF-α transcripts among transgenic lines. Total volume of lungs (LV) fixed by airway infusion at standard pressure was similar in transgenics and aged-matched non-transgenic mice (Fig. 1). Intrapulmonary bronchi and bronchioles made up a smaller percentage of LV in transgenics than in non-transgenics (Fig. 2). Pulmonary arteries and pulmonary veins were a smaller percentage of LV in transgenic mice than in non-transgenics (Fig. 3). Lung parenchyma (lung tissue free of large vessels and conducting airways) occupied a larger percentage of LV in transgenics than in non-transgenics (Fig. 4). The number of generations of branching in conducting airways was significantly reduced in transgenics as compared to non-transgenic mice. Alveolar air space size, as measured by mean linear intercept, was almost twice as large in transgenic mice as in non-transgenics, especially when different zones within the lung were compared (Fig. 5). Alveolar air space occupied a larger percentage of the lung parenchyma in transgenic mice than in non-transgenic mice (Fig. 6). Collagen abundance was estimated in histological sections as picro-Sirius red positive material by previously-published methods. In intrapulmonary conducting airways, collagen was 4.8% of the wall in transgenics and 4.5% of the wall in non-transgenic mice. Since airways represented a smaller percentage of the lung in transgenics, the volume of interstitial collagen associated with airway wall was significantly less. In intrapulmonary blood vessels, collagen was 8.9% of the wall in transgenics and 0.7% of the wall in non-transgenics. Since blood vessels were a smaller percentage of the lungs in transgenics, the volume of collagen associated with the walls of blood vessels was five times greater. In the lung parenchyma, collagen was 51.5% of the tissue volume in transgenics and 21.2% in non-transgenics. Since parenchyma was a larger percentage of lung volume in transgenics, but the parenchymal tissue was a smaller percent of the volume, the volume of collagen associated with parenchymal tissue was only slightly greater. We conclude that overexpression of TGF-α during lung maturation alters many aspects of lung development, including branching morphogenesis of the airways and vessels and alveolarization in the parenchyma. Further, the increases in visible collagen previously associated with pulmonary fibrosis due to the overexpression of TGF-α are a result of actual increases in amounts of collagen and in a redistribution of collagen within compartments which results from morphogenetic changes. These morphogenetic changes vary by lung compartment. Supported by HL20748, ES06700 and the Cystic Fibrosis Foundation.
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Yang, Jianqi, Alison N. DeVore, Daniel A. Fu, Mackenzie M. Spicer, Mengcheng Guo, Samantha G. Thompson, Katelin E. Ahlers-Dannen, Federica Polato, Andre Nussenzweig und Rory A. Fisher. „Rapid and precise genotyping of transgene zygosity in mice using an allele-specific method“. Life Science Alliance 6, Nr. 6 (10.04.2023): e202201729. http://dx.doi.org/10.26508/lsa.202201729.
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Precise determination of transgene zygosity is essential for use of transgenic mice in research. Because integration loci of transgenes are usually unknown due to their random insertion, assessment of transgene zygosity remains a challenge. Current zygosity genotyping methods (progeny testing, qPCR, and NGS-computational biology analysis) are time consuming, prone to error or technically challenging. Here, we developed a novel method to determine transgene zygosity requiring no knowledge of transgene insertion loci. This method applies allele-specific restriction enzyme digestion of PCR products (RE/PCR) to rapidly and reliably quantify transgene zygosity. We demonstrate the applicability of this method to three transgenic strains of mice (AtmTgC3001L,Nes-Cre, andSyn1-Cre) harboring a unique restriction enzyme site on either the transgene or its homologous sequence in the mouse genome. This method is as accurate as the gold standard of progeny testing but requires 2 d instead of a month or more. It is also exceedingly more accurate than the most commonly used approach of qPCR quantification. Our novel method represents a significant technical advance in determining transgene zygosities in mice.
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BABINET, CHARLES. „Transgenic Mice“. Journal of the American Society of Nephrology 11, suppl 2 (November 2000): S88—S94. http://dx.doi.org/10.1681/asn.v11suppl_2s88.
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Abstract. Stable integration into the mouse genome of exogenous genetic information, i.e., the creation of transgenic mice, has become a privileged way of analyzing gene function in normal development and pathology. Both gene addition and gene replacement may be performed. This has allowed, in particular, the creation of mice in which precise mutations are introduced into a given gene. Furthermore, in recent years, strategies that induce the expression of a mutation in a given type of cell and/or at a given time in development have been developed. Thus, the transgenic methodology affords a unique and irreplaceable tool for the study of mammalian development and biology and for the creation of animal models for human genetic diseases.
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Hickman-Davis, Judy M., und Ian C. Davis. „Transgenic mice“. Paediatric Respiratory Reviews 7, Nr. 1 (März 2006): 49–53. http://dx.doi.org/10.1016/j.prrv.2005.09.005.
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Friedman, Rick A., und Allen F. Ryan. „Transgenic Mice“. Otolaryngologic Clinics of North America 25, Nr. 5 (Oktober 1992): 1017–26. http://dx.doi.org/10.1016/s0030-6665(20)30922-1.
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PALMITER, R., und R. BRINSTER. „Transgenic mice“. Cell 41, Nr. 2 (Juni 1985): 343–45. http://dx.doi.org/10.1016/s0092-8674(85)80004-0.
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Westphal, Heiner. „Transgenic mice“. BioEssays 6, Nr. 2 (Februar 1987): 73–76. http://dx.doi.org/10.1002/bies.950060208.
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Starck, J., R. Sarkar, M. Romana, A. Bhargava, AL Scarpa, M. Tanaka, JW Chamberlain, SM Weissman und BG Forget. „Developmental regulation of human gamma- and beta-globin genes in the absence of the locus control region“. Blood 84, Nr. 5 (01.09.1994): 1656–65. http://dx.doi.org/10.1182/blood.v84.5.1656.1656.
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Abstract Two lines of transgenic mice carrying a normal 40-kb Kpn I beta-globin cluster transgene lacking the locus control region (LCR) were analyzed for the expression of human gamma- and beta-globin genes during mouse development. After RNase protection assays, the ratios of human G gamma- , A gamma-, or beta-mRNAs relative to endogenous mouse zeta + alpha mRNAs were obtained for each stage of development. The two gamma transgenes were expressed in day-11.5 blood (embryonic stage) and day- 13.5 blood (early fetal stage), but their expression was markedly decreased by day 16.5 of fetal life. Expression of the beta transgene was essentially absent at day 13.5, appeared at a low level by day 16.5, and was maximal by day 18.5, reaching a level similar to that observed in adult mice. Therefore, developmentally regulated expression of the human gamma- and beta-globin transgenes was obtained in the absence of the LCR. The relative expression of human gamma- and beta- globin genes was also examined in mice carrying 40-kb Kpn I beta- cluster transgenes with two different base substitutions associated with nondeletion forms of hereditary persistence of fetal hemoglobin (HPFH), -202 C-->G G gamma HPFH and -117 G-->A A gamma HPFH. The ratio of G gamma- to beta-globin transcripts was markedly increased in red blood cells of adult mice from three different lines carrying the transgene with the -202 G gamma HPFH mutation. This result confirms our previous preliminary results (Tanaka et al: Ann NY Acad Sci, 612:167, 1990) indicating that the -202 G gamma HPFH phenotype was reproduced in transgenic mice. The relatively low levels of G gamma-mRNA expression in adult mice carrying the non-HPFH transgene excludes a major influence of the 3′ beta-globin enhancer, present upstream of the G gamma gene because of the tandem repeat insertion, as a factor in the persistent G gamma gene expression observed in blood of adult mice carrying the -202 G gamma HPFH transgene. This conclusion is also supported by the fact that, in mice carrying the -117 A gamma HPFH transgene, G gamma-globin mRNA was detected in blood of adult animals only at low levels similar to that observed in the non-HPFH lines. However, the A gamma-HPFH phenotype was not reproduced in the transgenic lines carrying the -117A gamma HPFH mice.
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Starck, J., R. Sarkar, M. Romana, A. Bhargava, AL Scarpa, M. Tanaka, JW Chamberlain, SM Weissman und BG Forget. „Developmental regulation of human gamma- and beta-globin genes in the absence of the locus control region“. Blood 84, Nr. 5 (01.09.1994): 1656–65. http://dx.doi.org/10.1182/blood.v84.5.1656.bloodjournal8451656.
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Two lines of transgenic mice carrying a normal 40-kb Kpn I beta-globin cluster transgene lacking the locus control region (LCR) were analyzed for the expression of human gamma- and beta-globin genes during mouse development. After RNase protection assays, the ratios of human G gamma- , A gamma-, or beta-mRNAs relative to endogenous mouse zeta + alpha mRNAs were obtained for each stage of development. The two gamma transgenes were expressed in day-11.5 blood (embryonic stage) and day- 13.5 blood (early fetal stage), but their expression was markedly decreased by day 16.5 of fetal life. Expression of the beta transgene was essentially absent at day 13.5, appeared at a low level by day 16.5, and was maximal by day 18.5, reaching a level similar to that observed in adult mice. Therefore, developmentally regulated expression of the human gamma- and beta-globin transgenes was obtained in the absence of the LCR. The relative expression of human gamma- and beta- globin genes was also examined in mice carrying 40-kb Kpn I beta- cluster transgenes with two different base substitutions associated with nondeletion forms of hereditary persistence of fetal hemoglobin (HPFH), -202 C-->G G gamma HPFH and -117 G-->A A gamma HPFH. The ratio of G gamma- to beta-globin transcripts was markedly increased in red blood cells of adult mice from three different lines carrying the transgene with the -202 G gamma HPFH mutation. This result confirms our previous preliminary results (Tanaka et al: Ann NY Acad Sci, 612:167, 1990) indicating that the -202 G gamma HPFH phenotype was reproduced in transgenic mice. The relatively low levels of G gamma-mRNA expression in adult mice carrying the non-HPFH transgene excludes a major influence of the 3′ beta-globin enhancer, present upstream of the G gamma gene because of the tandem repeat insertion, as a factor in the persistent G gamma gene expression observed in blood of adult mice carrying the -202 G gamma HPFH transgene. This conclusion is also supported by the fact that, in mice carrying the -117 A gamma HPFH transgene, G gamma-globin mRNA was detected in blood of adult animals only at low levels similar to that observed in the non-HPFH lines. However, the A gamma-HPFH phenotype was not reproduced in the transgenic lines carrying the -117A gamma HPFH mice.
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Faerman, A., I. Barash, R. Puzis, M. Nathan, D. R. Hurwitz und M. Shani. „Dramatic heterogeneity of transgene expression in the mammary gland of lactating mice: a model system to study the synthetic activity of mammary epithelial cells.“ Journal of Histochemistry & Cytochemistry 43, Nr. 5 (Mai 1995): 461–70. http://dx.doi.org/10.1177/43.5.7730585.
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We studied the expression of human serum albumin (HSA) driven by the ovine beta-lactoglobulin promoter in the mammary glands of lactating mice from five independent transgenic strains, by employing combined in situ hybridization and immunostaining techniques. Four strains displayed a heterogeneous pattern of expression: mice of strains 91 and 92 expressed the transgene in only a fraction of the lobules, whereas in strains 69 and 83 all lobules contained cells expressing HSA. In all four strains the patterns of expression within expressing lobules corresponded to the morphology of alveolar cells and to the extent of local milk secretion, suggesting that filling of alveolus with secreted material was accompanied by asynchronous downregulation of transgene expression. In situ hybridization to the endogenous milk protein genes alpha-lactalbumin, beta-casein, and whey acidic protein revealed a uniform pattern of expression in lactating mammary glands of transgeneic and in four out of five non-transgeneic mice. In the fifth control mouse, we detected downregulation of gene expression in lobules containing alveoli distended by secreted milk. The pattern of expression of the three endogenous genes was greatly disturbed after a short (3-hr) unilateral closure of mammary glands, and very much resembled the pattern of expression of the HSA transgenes. These results demonstrate that transgeneic mice provide a useful model to study the factors that regulate the synthetic activity of mammary epithelial cells.
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Tsao, B. P., K. Ohnishi, H. Cheroutre, B. Mitchell, M. Teitell, P. Mixter, M. Kronenberg und B. H. Hahn. „Failed self-tolerance and autoimmunity in IgG anti-DNA transgenic mice.“ Journal of Immunology 149, Nr. 1 (01.07.1992): 350–58. http://dx.doi.org/10.4049/jimmunol.149.1.350.
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Abstract Transgenic mice were generated that express both the H and L chain genes derived from a hybridoma secreting an IgG2a mAb specific for ds- and ssDNA. This hybridoma is derived from a lupus mouse and can accelerate nephritis in young NZB x NZW F1 female mice and induce clinical nephritis in BALB/c mice. Some transgenic B cells did not exhibit allelic exclusion; they expressed both transgene-derived IgG and endogenous IgM intracellularly. Most of the B cells in transgenic mice expressed endogenous IgM, some of them expressed low levels of IgG on cell membranes. The transgenic mice, created in a strain not prone to SLE, expressed elevated serum IgG anti-DNA, and some developed clinical nephritis. The affinity of the spontaneously secreted IgG antibodies for dsDNA were similar in nephritic NZB x NZW F1 and transgenic mice. In contrast to the nontransgenic littermates, immunization of transgenic mice with murine DNA further enhanced serum levels of IgG anti-DNA in transgenic mice. Therefore, expression of transgene-encoded IgG anti-DNA mainly in the secreted form does not provide the signals necessary for allelic exclusion or self-tolerance. Expression of this Ig is sufficient to induce a mild form of autoimmune disease.
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Altmann, D. M., D. C. Douek, A. J. Frater, C. M. Hetherington, H. Inoko und J. I. Elliott. „The T cell response of HLA-DR transgenic mice to human myelin basic protein and other antigens in the presence and absence of human CD4.“ Journal of Experimental Medicine 181, Nr. 3 (01.03.1995): 867–75. http://dx.doi.org/10.1084/jem.181.3.867.
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Analysis of HLA class II transgenic mice has progressed in recent years from analysis of single chain HLA class II transgenes with expression of mixed mouse/human heterodimers to double transgenic mice expressing normal human heterodimers. Previous studies have used either HLA transgenic mice in which there is a species-matched interaction with CD4 or mice which lack this interaction. Since both systems are reported to generate HLA-restricted responses, the matter of the requirement for species-matched CD4 remains unclear. We have generated triple transgenic mice expressing three human transgenes, DRA, DRB, and CD4, and compared HLA-restricted responses to peptide between human-CD4+ (Hu-CD4+) and Hu-CD4- littermates. We saw no difference between Hu-CD4+ and Hu-CD4- groups, supporting the notion that for some responses at least the requirement for species-matched CD4 may not be absolute. Evidence for positive selection of mouse T cell receptors in HLA-DR transgenic mice came both from the acquisition of new, HLA-restricted responses to various peptides and from an increased frequency of T cells using the TCR V beta 4 gene segment. An important goal with respect to the analysis of function in HLA transgenic mice is the clarification of mechanisms which underpin the recognition of self-antigens in human autoimmune disease. As a first step towards 'humanized' disease models in HLA transgenic mice, we analyzed the responses of HLA-DR transgenic mice to the human MPB 139-154 peptide which has been implicated as an epitope recognized by T cells of multiple sclerosis patients. We obtained T cell responses to this epitope in transgenic mice but not in nontransgenic controls. This study suggests that HLA transgenic mice will be valuable in the analysis of HLA-restricted T cell epitopes implicated in human disease and possibly in the design of new disease models.
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Hazel, Mark, Robert C. Cooksey, Deborah Jones, Glendon Parker, John L. Neidigh, Bryan Witherbee, Eric A. Gulve und Donald A. McClain. „Activation of the Hexosamine Signaling Pathway in Adipose Tissue Results in Decreased Serum Adiponectin and Skeletal Muscle Insulin Resistance“. Endocrinology 145, Nr. 5 (01.05.2004): 2118–28. http://dx.doi.org/10.1210/en.2003-0812.
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Abstract Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase) in muscle and adipose tissue of transgenic mice was previously shown to result in insulin resistance and hyperleptinemia. Explanted muscle from transgenic mice was not insulin resistant in vitro, suggesting that muscle insulin resistance could be mediated by soluble factors from fat tissue. To dissect the relative contributions of muscle and fat to hexosamine-induced insulin resistance, we overexpressed glutamine:fructose-6-phosphate amidotransferase 2.5-fold, specifically in fat under control of the aP2 promoter. Fasting glucose, insulin, and triglycerides were unchanged in the transgenic mice; leptin and β-hydroxybutyrate levels were 91% and 29% higher, respectively. Fasted transgenic mice have mild glucose intolerance and skeletal muscle insulin resistance in vivo. In fasting transgenic mice, glucose disposal rates with hyperinsulinemia were decreased 27% in females and 10% in males. Uptake of 2-deoxy-d-glucose into muscle was diminished by 45% in female and 21% in male transgenics. Serum adiponectin was also lower in the fasted transgenics, by 37% in females and 22% in males. TNFα and resistin mRNA levels in adipose tissue were not altered in the fasted transgenics; levels of mRNA for leptin were increased and peroxisome proliferator-activated receptor γ decreased. To further explore the relationship between adiponectin and insulin sensitivity, we examined mice that have been refed for 6 h after a 24-h fast. Refeeding wild-type mice resulted in decreased serum adiponectin and increased leptin. In transgenic mice, however, the regulation of these hormones by refeeding was lost for adiponectin and diminished for leptin. Refed transgenic female and male mice no longer exhibited decreased serum adiponectin in the refed state, and they were no longer insulin resistant as by lower or unchanged insulin and glucose levels. We conclude that increased hexosamine levels in fat, mimicking excess nutrient delivery, are sufficient to cause insulin resistance in skeletal muscle. Changes in serum adiponectin correlate with the insulin resistance of the transgenic animals.
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Zhou, R., H. Flaswinkel, MR Schneider, H. Lahm, A. Hoeflich, R. Wanke und E. Wolf. „Insulin-like growth factor-binding protein-4 inhibits growth of the thymus in transgenic mice“. Journal of Molecular Endocrinology 32, Nr. 2 (01.04.2004): 349–64. http://dx.doi.org/10.1677/jme.0.0320349.
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Numerous in vitro studies have demonstrated that IGF-binding protein (IGFBP)-4 is a consistent inhibitor of IGF actions. In order to investigate the functions of IGFBP-4 in vivo, transgenic mice were generated by microinjection of a transgene, in which the murine Igfbp4 cDNA is driven by the H-2K(b) promoter, and followed by a splicing cassette and polyadenylation signal of the human beta-globin gene. Transgene mRNA was expressed ubiquitously, and elevated IGFBP-4 protein was detected in the spleen, thymus, kidney and lung of transgenic mice. The activities of serum IGFBPs were not changed in transgenic mice. Immunohistochemical studies revealed transgene expression predominantly in the thymic medulla and red pulp of the spleen. Body weight and the weights of the spleen, kidney and lung of transgenic mice were not different from controls. In contrast, the thymus of transgenic mice showed a significantly reduced weight and cortex volume. In transgenic thymus and spleen, cell proliferation was inhibited and apoptosis was stimulated. Transgenic mice showed normal T- and B-cell development and normal basal plasma immunoglobulin levels. In conclusion, overexpression of IGFBP-4 inhibits growth of the thymus. IGFBP-4 excess inhibits cell proliferation and stimulates apoptosis in lymphoid tissues, but does not affect lymphocyte development. These findings suggest that IGFBP-4 is a potential growth inhibitor of lymphoid tissues.
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Roth, P. E., L. Doglio, J. T. Manz, J. Y. Kim, D. Lo und U. Storb. „Immunoglobulin gamma 2b transgenes inhibit heavy chain gene rearrangement, but cannot promote B cell development.“ Journal of Experimental Medicine 178, Nr. 6 (01.12.1993): 2007–21. http://dx.doi.org/10.1084/jem.178.6.2007.
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Transgenic mice with a gamma 2b transgene were produced to investigate whether gamma 2b can replace mu in the development of B lymphocytes. Transgenic gamma 2b is present on the surface of B cells. Young transgenic mice have a dramatic decrease in B cell numbers, however, older mice have almost normal B cell numbers. Strikingly, all gamma 2b-expressing B cells in the spleen also express mu. The same is true for mice with a hybrid transgene in which the mu transmembrane and intracytoplasmic sequences replace those of gamma 2b (gamma 2b-mumem). The B cell defect is not due to toxicity of gamma 2b since crosses between gamma 2b transgenic and mu transgenic mice have normal numbers of B cells. Presence of the gamma 2b transgene strongly enhances the feedback inhibition of endogenous heavy chain gene rearrangement. Light chain genes are expressed normally, and the early expression of transgenic light chains does not improve B cell maturation. When the endogenous mu locus is inactivated, B cells do not develop at all in gamma 2b transgenic mice. The data suggest that gamma 2b cannot replace mu in promoting the developmental maturation of B cells, but that it can cause feedback inhibition of heavy chain gene rearrangement. Thus, the signals for heavy chain feedback and B cell maturation appear to be different.
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Nussenzweig, M. C., A. C. Shaw, E. Sinn, J. Campos-Torres und P. Leder. „Allelic exclusion in transgenic mice carrying mutant human IgM genes.“ Journal of Experimental Medicine 167, Nr. 6 (01.06.1988): 1969–74. http://dx.doi.org/10.1084/jem.167.6.1969.
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Expression of the membrane-bound version of the human mu chain in transgenic mice results in the allelic exclusion of endogenous mouse Ig heavy chain genes (6). The secreted version of the human Ig transgene has no such effect. F1 hybrid animals that carry transgenes for both secreted and membrane-bound human mu chains produce both forms of the human heavy chain while strongly suppressing endogenous mouse mu expression. The simultaneous expression of the two rearranged transgenes in primary B cells suggests that allelic exclusion operates before the formation of a second functionally rearranged heavy chain gene in vivo.
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Loiacono, Christie M., Robert Myers und William J. Mitchell. „Neurons Differentially Activate the Herpes Simplex Virus Type 1 Immediate-Early Gene ICP0 and ICP27 Promoters in Transgenic Mice“. Journal of Virology 76, Nr. 5 (01.03.2002): 2449–59. http://dx.doi.org/10.1128/jvi.76.5.2449-2459.2002.
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ABSTRACT Herpes simplex virus type 1 (HSV-1) immediate-early (IE) proteins are required for the expression of viral early and late proteins. It has been hypothesized that host neuronal proteins regulate expression of HSV-1 IE genes that in turn control viral latency and reactivation. We investigated the ability of neuronal proteins in vivo to activate HSV-1 IE gene promoters (ICP0 and ICP27) and a late gene promoter (gC). Transgenic mice containing IE (ICP0 and ICP27) and late (gC) gene promoters of HSV-1 fused to the Escherichia coli β-galactosidase coding sequence were generated. Expression of the ICP0 and ICP27 reporter transgenes was present in anatomically distinct subsets of neurons in the absence of viral proteins. The anatomic locations of β-galactosidase-positive neurons in the brains of ICP0 and ICP27 reporter transgenic mice were similar and included cerebral cortex, lateral septal nucleus, cingulum, hippocampus, thalamus, amygdala, and vestibular nucleus. Trigeminal ganglion neurons were positive for β-galactosidase in adult ICP0 and ICP27 reporter transgenic mice. The ICP0 reporter transgene was differentially regulated in trigeminal ganglion neurons depending upon age. β-Galactosidase-labeled cells in trigeminal ganglia and cerebral cortex of ICP0 and ICP27 reporter transgenic mice were confirmed as neurons by double labeling with antineurofilament antibody. Nearly all nonneuronal cells in ICP0 and ICP27 reporter transgenic mice and all neuronal and nonneuronal cells in gC reporter transgenic mice were negative for β-galactosidase labeling in the absence of HSV-1. We conclude that factors in neurons are able to differentially regulate the HSV-1 IE gene promoters (ICP0 and ICP27) in transgenic mice in the absence of viral proteins. These findings are important for understanding the regulation of the latent and reactivated stages of HSV-1 infection in neurons.
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Rath, S., A. Nisonoff, E. Selsing und J. M. Durdik. „B cell abnormalities induced by a mu Ig transgene extend to L chain isotype usage.“ Journal of Immunology 146, Nr. 8 (15.04.1991): 2841–46. http://dx.doi.org/10.4049/jimmunol.146.8.2841.
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Abstract We have analyzed the phenotype of B cell populations from mice transgenic for a rearranged Ig mu H chain gene. We find a decrease in the number of B cells in the spleens of these mice. Transgenic B cells have decreased surface levels of both IgM and IgD. The circulating IgM in these mice is 3- to 10-fold enriched in lambda L chains, compared with that in non-transgenic mice. Analysis of IgM-producing hybridomas, from transgenic mice that express the transgene at high levels, demonstrates that this higher lambda frequency is observed in transgene-nonexpressing as well as transgene-expressing hybridomas. A partial loss of L chain isotype exclusion is also noted in these hybridomas, and a significant proportion of primary B cells expressing both kappa and lambda L chains on their surface can be demonstrated. These findings suggest an ability of the transgenic Ig H chain to affect events in B cell ontogeny beyond the H chain locus. Our results support a quantitative model of exclusion for both the H chain alleles and the L chain isotypes.
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Clutter, A. C., D. Pomp und J. D. Murray. „Quantitative Genetics of Transgenic Mice: Components of Phenotypic Variation in Body Weights and Weight Gains“. Genetics 143, Nr. 4 (01.08.1996): 1753–60. http://dx.doi.org/10.1093/genetics/143.4.1753.
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Abstract Transgenic mice possessing an ovine growth hormone gene were used to study the effects of elevated growth hormone on quantitative genetic variation. Males hemizygous for the transgene were mated to wild-type females to produce half- and full-sib families in which approximately half the progeny were transgenic and half were wild type. Analyses of body weights at 3–10 weeks, and weight gains from 3 to 6, and 6 to 10 weeks produced estimates of the proportion of total variance due to additive genetic effects (h2) and common litter effects (c2), and the genetic correlation between transgenic and wild-type expression of each trait. At 10 weeks, body weight of transgenics exceeded that of wild types by 26 and 49% in males and females, respectively. Estimated genetic variances in the transgenic group were significantly greater than zero for body weights at most ages and for both measurements of gain. Common litter effects accounted for a similar proportion of variation in the wild-type and transgenic groups. Additive genetic correlations between wild-type and transgenic expression of body weights tended to decline with age, indicating that a partially different array of genes may have begun to affect body weight in the transgenic group.
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Rudin, C. M., J. Hackett und U. Storb. „Precursors of both conventional and Ly-1 B cells can escape feedback inhibition of Ig gene rearrangement.“ Journal of Immunology 146, Nr. 9 (01.05.1991): 3205–10. http://dx.doi.org/10.4049/jimmunol.146.9.3205.
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Abstract Experiments with transgenic mice carrying rearranged Ig transgenes have shown that membrane bound Ig molecules cause feedback inhibition of endogenous Ig gene rearrangement. However, this inhibition is never complete. It has been postulated that escape from feedback may be a property of the Ly-1 B cell subset, whereas rearrangement of endogenous Ig genes may be completely inhibited in conventional B cells. This possibility was investigated in transgenic mice carrying a lambda transgene under the control of the H chain enhancer. It was found that kappa producing B cells in these lambda transgenic mice were for the most part, although not exclusively, of the conventional B cell phenotype. Examination of peritoneal exudate cells revealed that a large proportion of Ly-1 B cells also express kappa. Adoptive transfer of bone marrow from adult lambda transgenic mice, a source of conventional B cell precursors, resulted in the production of relatively high levels of serum kappa 2 to 3 mo after transfer into recipient SCID mice. A high proportion of donor B cells in the spleen produced endogenous kappa protein with or without co-production of lambda. It is concluded that precursors of both conventional and Ly-1 B cells can escape feedback inhibition of L chain gene rearrangement.
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Imanishi-Kari, T., C. A. Huang, J. Iacomini und N. Yannoutsos. „Endogenous Ig production in mu transgenic mice. II. Anti-Ig reactivity and apparent double allotype expression.“ Journal of Immunology 150, Nr. 8 (15.04.1993): 3327–46. http://dx.doi.org/10.4049/jimmunol.150.8.3327.
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Abstract In 17.2.25 mu transgenic mice (M54, M95), many of the expressed Ig, whether encoded by the transgene or endogenous H chain genes, react with Ig. IgM antibodies encoded by the 17.2.25 mu transgene transfected into J558L myeloma cells are also Ig reactive. In addition, anti-Ig reactivity was manifested by antibodies of the IgM, IgG, and IgA isotypes from the transgenic mice, suggesting that this characteristic reactivity is associated with VH and VL domains of these antibodies. These antibodies bind the (Fab')2 fragment of mouse IgG1 mAb known to be directed against C mu allotypic determinants. This finding could account for the so called "double producer" B cells found in mu transgenic mice and previously identified in serologic assays conducted with two different anti-mu allotypic reagents. In transgenic mice, a high frequency of the antibodies encoded by the transgene or endogenous H chain genes react with polyclonal and monoclonal antiidiotypic antibodies raised against the 17.2.25 Id. The idiotypic and/or antiidiotypic reactivity displayed by antibodies derived from these transgenic mice is similar to that of antibodies expressed by neonatal B cells of normal mice. Thus, our data suggest that transgene expression can play an important role in shaping the endogenous repertoire of antibody specificities.
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Schanberg, L. E., D. M. Lee, D. E. Fleenor, R. E. Ware, D. D. Patel, B. F. Haynes und R. E. Kaufman. „Characterization of human CD7 transgenic mice.“ Journal of Immunology 155, Nr. 5 (01.09.1995): 2407–18. http://dx.doi.org/10.4049/jimmunol.155.5.2407.
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Abstract CD7 is a 40-kDa transmembrane glycoprotein member of the lg gene superfamily expressed on most peripheral blood T lymphocytes and NK cells. CD7 is also expressed on myeloid, NK, B, and T cell precursors during adult hematopoiesis. Because Thy-1 is absent in human thymocytes and peripheral blood T cells and shows structural similarities to the human CD7 gene, we have suggested that human CD7 may be a functional homologue in humans of mouse Thy-1. To study the tissue-specific expression of the CD7 gene utilizing its own promoter, we constructed transgenic mice that contained both the coding and flanking regions of the human CD7 gene. We found that human CD7 was expressed in transgenic mice in T, B, NK, and myeloid lineages and was induced with T cell activation. Unlike the expression of CD7 in humans, the CD7 transgene was present on mature B lymphocytes and macrophages. Like mouse Thy-1, transgenic human CD7 was expressed in immature and mature T cells and in Sca-1+ bone marrow mononuclear cells. Unlike mouse Thy-1, the human CD7 transgene was not expressed in mouse brain or fibroblasts. The human CD7 transgene was expressed during fetal development before mouse Thy-1 in fetal liver mononuclear cells. Expression of the human CD7 transgene did not alter mouse thymopiesis or Thy-1 expression. Taken together, these data demonstrated that the CD7 transgene contained sufficient regulatory regions to direct hematopoietic expression and mitogenic induction. The pattern of CD7 transgene expression more closely resembled that of CD7 in humans than that of mouse Thy-1.
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Robbiani, Davide F., Kaity Colon, Kruti Naik, Helen Nickerson, Maurizio Affer, Marta Chesi und Peter Leif Bergsagel. „Enforced BCL6 Expression Inhibits B Cell Development in Vivo.“ Blood 104, Nr. 11 (16.11.2004): 1535. http://dx.doi.org/10.1182/blood.v104.11.1535.1535.
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Abstract The B-Cell Lymphoma 6 (BCL6) gene encodes for a zinc finger motifs containing transcriptional repressor that is frequently dysregulated by chromosomal translocations in germinal center lymphomas. A putative protooncogene, its transforming ability in vivo was reported in I-mu-HA-BCL6 knock-in mice by Cattoretti et al last year. We also tested this assumption in transgenic mice expressing BCL6 in B cells under the control of kappa light chain regulatory elements. We replaced the murine C-kappa locus with the 16kb human BCL6 genomic locus in a construct containing the murine kappa light chain regulatory elements (Vk, EiK, 3′RR). While control transgenics were readily obtained (5/32 founders), only 3/68 founders were positive for the BCL6 transgene, of which only one (bearing a single copy of the transgene) was able to transmit the transgene to its progeny, thus suggesting embryonal toxicity of exogenous BCL6. In the bone marrow, flow cytometry revealed a nearly complete block of B cell development at the pro-B to pre-B transition. This was also the stage at which we first detected expression of EGFP in control reporter mice that were generated in parallel. Spleens of transgenic mice weighed about 50% of control spleens and less than 5% of splenocytes were CD19+ B cells. These were IgM high, IgD intermediate, corresponding to an immature B cell phenotype. Lymph nodes were smaller and B cells barely detected. Peyers’ patches were not visible. Combined, our analysis of 6–8 weeks old VkHABCL6 transgenic mice reveals that enforced expression of BCL6 early in development results in a profound block of B lymphocyte differentiation. How transgenic BCL6 modulates this effect at the transcriptional level remains to be investigated. To test the oncogenic potential of BCL6 in B cells, it will be interesting to precisely turn on this gene in the germinal center.
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Yukawa, K., H. Kikutani, T. Inomoto, M. Uehira, S. H. Bin, K. Akagi, K. Yamamura und T. Kishimoto. „Strain dependency of B and T lymphoma development in immunoglobulin heavy chain enhancer (E mu)-myc transgenic mice.“ Journal of Experimental Medicine 170, Nr. 3 (01.09.1989): 711–26. http://dx.doi.org/10.1084/jem.170.3.711.
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The transgenic mice were produced by injecting eggs of B6 and C3H/HeJ mice with the human E mu-myc gene. Preferential development of B lymphomas was observed in the B6 transgenic mice, whereas the C3H/HeJ transgenic mice developed mostly T lymphomas. The phenotypic activation of B lineage cells but not of T lineage cells was detected in the prelymphomatous transgenic mice of both strains. The transgene was similarly expressed in B and T cells of the transgenic mice of both strains. These results suggest that a high incidence of T lymphomas in the C3H/HeJ transgenic mice may not be due to the preferential activation of or the preferential E mu-myc expression in T lymphocytes. When the bone marrow or fetal liver cells from the prelymphomatous transgenic mice of both strains were transferred into irradiated normal C3H/HeJ mice, most of the recipients developed T lymphomas. Moreover, even when irradiated B6 mice received the hematopoietic stem cells from the prelymphomatous B6 transgenic mice, the incidence of T lymphoma increased up to 50%. These findings suggest that B6 and C3H/HeJ mice might provide the environment that supports the development or growth of B and T lymphomas, respectively, and that such an environment could be modified by irradiation of the mice.
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Tsika, G. L., J. L. Wiedenman, L. Gao, J. J. McCarthy, K. Sheriff-Carter, I. D. Rivera-Rivera und R. W. Tsika. „Induction of beta-MHC transgene in overloaded skeletal muscle is not eliminated by mutation of conserved elements“. American Journal of Physiology-Cell Physiology 271, Nr. 2 (01.08.1996): C690—C699. http://dx.doi.org/10.1152/ajpcell.1996.271.2.c690.
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Mechanical overload leads to hypertrophy, increased type I fiber composition, and beta-myosin heavy chain (beta-MHC) induction in the fast-twitch plantaris muscle. To better understand the mechanism(s) involved in beta-MHC induction, we have examined inducible expression of transgenes carrying the simultaneous mutation of three DNA regulatory subregions [muscle CAT (MCAT), C-rich, and beta e3] in the context of either 5,600-base pair (bp; beta 5.6mut3) or 600-bp (beta 0.6mut3) beta-MHC promoter in overloaded plantaris muscles of transgenic mice. Protein extract from mechanically overloaded plantaris muscle of mice, harboring either mutant transgene beta 5.6mut3 or beta 0.6mut3, showed an unexpected 2.8- to 4.5-fold increase in chloramphenicol acetyltransferase (CAT) specific activity relative to their respective controls. Similar results were obtained with wild-type (wt) beta-MHC transgenes (beta 5.6wt, beta 0.6wt). Histochemical staining for both myofibrillar ATPase and CAT activity and CAT immunohistochemistry revealed a striking increase in type I fibers and that CAT expression was restricted to these fibers in overloaded plantaris muscle of beta 5.6mut3 transgenic mice. Our transgenic data suggest that beta-MHC transgenes, and perhaps the endogenous beta-MHC gene, are induced by mechanical overload via a mechanism(s) that does not exclusively require the MCAT, C-rich, or beta e3 subregions.
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Brooks, A. R., B. P. Nagy, S. Taylor, W. S. Simonet, J. M. Taylor und B. Levy-Wilson. „Sequences containing the second-intron enhancer are essential for transcription of the human apolipoprotein B gene in the livers of transgenic mice“. Molecular and Cellular Biology 14, Nr. 4 (April 1994): 2243–56. http://dx.doi.org/10.1128/mcb.14.4.2243-2256.1994.
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To identify DNA sequence elements from the human apolipoprotein B (apoB) gene required for high-level, correct tissue-specific expression in transgenic mice, we made several constructs that included one or more of the key regulatory elements that were previously characterized with cultured liver-derived and intestine-derived cell lines. Our data show that the apoB promoter alone (-898 to +121) is not sufficient to direct transcription in transgenic mice. An enhancer located in the second intron is absolutely required to specify transcription by the homologous apoB promoter in the livers of transgenic mice; this enhancer does not direct transcription in the small intestines. Thus, the elements controlling transcriptional activation of the apoB gene in the liver and the intestine in vivo are distinct and separable. Analysis of the DNase I hypersensitivity of the integrated human transgenes in various lines of expressing and nonexpressing mice suggests that the formation of DH4, a strong hypersensitive site in intron 2, may be a prerequisite for hepatic expression of the apoB gene. Nuclear matrix association regions (MARs) of the apoB gene may play a role in transgene expression. Constructs including MAR sequences displayed higher levels of expression than those lacking them. However, these MARs did not completely insulate the associated transgenes from position effects.
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Brooks, A. R., B. P. Nagy, S. Taylor, W. S. Simonet, J. M. Taylor und B. Levy-Wilson. „Sequences containing the second-intron enhancer are essential for transcription of the human apolipoprotein B gene in the livers of transgenic mice.“ Molecular and Cellular Biology 14, Nr. 4 (April 1994): 2243–56. http://dx.doi.org/10.1128/mcb.14.4.2243.
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To identify DNA sequence elements from the human apolipoprotein B (apoB) gene required for high-level, correct tissue-specific expression in transgenic mice, we made several constructs that included one or more of the key regulatory elements that were previously characterized with cultured liver-derived and intestine-derived cell lines. Our data show that the apoB promoter alone (-898 to +121) is not sufficient to direct transcription in transgenic mice. An enhancer located in the second intron is absolutely required to specify transcription by the homologous apoB promoter in the livers of transgenic mice; this enhancer does not direct transcription in the small intestines. Thus, the elements controlling transcriptional activation of the apoB gene in the liver and the intestine in vivo are distinct and separable. Analysis of the DNase I hypersensitivity of the integrated human transgenes in various lines of expressing and nonexpressing mice suggests that the formation of DH4, a strong hypersensitive site in intron 2, may be a prerequisite for hepatic expression of the apoB gene. Nuclear matrix association regions (MARs) of the apoB gene may play a role in transgene expression. Constructs including MAR sequences displayed higher levels of expression than those lacking them. However, these MARs did not completely insulate the associated transgenes from position effects.
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Rimm, I. J., T. Ghayur, D. L. Gasser, K. Rosenkrantz, S. J. Burakoff, J. G. Seidman und J. L. Ferrara. „Alloreactive lymphocytes from T cell receptor (beta-chain) transgenic mice do not mediate a graft-versus-host reaction.“ Journal of Immunology 146, Nr. 4 (15.02.1991): 1130–33. http://dx.doi.org/10.4049/jimmunol.146.4.1130.
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Abstract The injection of mature T cells into a tolerant or immunocompromised allogeneic host animal produces a graft versus host response (GVHR) that can result in splenomegaly, immunosuppression and death of the host animal. We demonstrate here that lymphocytes from T cell receptor beta-chain (TCR-beta) transgenic mice, in which the expression of the transgene inhibits endogenous beta- and gamma-gene rearrangements and thus causes abnormal T cell development, are unable to mediate a GVHR. The GVHR was measured after the injection of lymphocytes from transgenic mice into normal F1 mice and also after transplantation of bone marrow and lymphocytes from transgenic mice into lethally irradiated F1 recipients. In both systems, cells from transgenic mice failed to produce a significant GVHR. Cells from the transgenic mice were able to recognize the foreign histocompatibility Ag of the host in vitro and in vivo although the transgenic mice rejected skin grafts more slowly than controls. Thus, lymphocytes from transgenic mice were unable to produce a GVHR despite the presence of alloreactive T cells. These results suggest that lymphocytes from TCR-beta transgenic mice fail to mediate a GVHR either because lymphocytes with a single transgenic TCR-beta chain have a limited ability to recognize allogeneic cells in vivo or because the transgenic mice lack lymphocyte subsets that are important for the mediation of a GVHR.
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Seery, John P., Eddie C. Y. Wang, Victoria Cattell, Joseph M. Carroll, Michael J. Owen und Fiona M. Watt. „A Central Role for αβ T Cells in the Pathogenesis of Murine Lupus“. Journal of Immunology 162, Nr. 12 (15.06.1999): 7241–48. http://dx.doi.org/10.4049/jimmunol.162.12.7241.
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Abstract We have previously shown that female transgenic mice expressing IFN-γ in the epidermis, under the control of the involucrin promoter, develop inflammatory skin disease and a form of murine lupus. To investigate the pathogenesis of this syndrome, we generated female IFN-γ transgenic mice congenitally deficient in either αβ or γδ T cells. TCRδ−/− transgenics continued to produce antinuclear autoantibodies and to develop severe kidney lesions. In contrast, TCRβ−/− IFN-γ transgenic mice failed to produce antinucleosome, anti-dsDNA, or antihistone autoantibodies, and kidney disease was abolished. Both αβ- and γδ-deficient transgenics continued to develop IFN-γ-associated skin disease, lymphadenopathy, and splenomegaly. The data show that the autoantibody-mediated pathology of murine lupus in IFN-γ transgenic mice is completely αβ T cell dependent and that γδ T cells cannot drive autoantibody production. These results imply that production of antinuclear autoantibodies in IFN-γ transgenic animals is Ag driven, and we identified clusters of apoptotic cells in the epidermis of the mice as a possible source of self Ags. Our findings emphasize the relevance of this murine lupus model to the human disease.
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Ho, Wanting, Wanming Zhao und Zhizhuang Joe Zhao. „Transgene Dose- and Age-Dependent Development of Myeloproliferative Neoplasm Phenotypes In JAK2V617F Transgene Mice“. Blood 116, Nr. 21 (19.11.2010): 1980. http://dx.doi.org/10.1182/blood.v116.21.1980.1980.
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Abstract Abstract 1980 Myeloproliferative neoplasms (MPNs) are heterogeneous hematologic disorders represented by three main phenotypes: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The major molecular lesion in these diseases is JAK2V617F, which occurs in over 95% patients with PV and in over 50% of patients with ET or PMF. The pathogenic effects of JAK2V617F have been demonstrated by retrovirus-mediated gene transfer, transgenic, and knock-in mouse models, but the precise mode of JAK2V617F action is not clear. Interestingly, in the knock-in model, expression of JAK2V617F causes severe PV-like disease but not ET-like phenotype as seen in patients. To verify the pathogenic role of JAK2V617F, we further characterized the phenotypes of three lines of JAK2V617F transgenic mice generated by using the vav gene promoter which drives expression of transgenes in the hematopoietic system. These mice developed MPN-like phenotypes in a transgene dose- and age-dependent manner. Line A mice have a JAK2V617F gene copy number of 13; they develop MPN phenotype with marked increases in blood counts and enlarged spleens as early as 4–6 weeks after birth. In contrast, lines B and D mice have a transgene copy number of 2 and 1, respectively, and it takes nearly 70 weeks for these mice to show MPN-like phenotypes. The phenotype of line A mice is particularly noteworthy. Essentially all the hemizygous line A mice displayed an ET-like phenotype with marked elevations in platelet counts (usually over 4000×109/L by the age of 15 weeks), but only a slight increase in red cell and white cell counts. In contrast, all the homozygous mice exhibited a clear PV-like phenotype with elevations in all three types of blood cells, although their platelets hardly ever went over 4000×109/L. The hemizygous mice developed myelofibrosis after 30 weeks while the homozygous mice showed the symptom within only 10 weeks. As expected, the increased blood cell counts and formation of myelofibrosis are associated with mobilization of hematopoietic stem/progenitor cells to peripheral hematopoietic tissues (blood, spleen, and liver). By conducting stem cell transplant experiments, we further proved that JAK2V617F-induced ET and PV-like phenotypes are transplantable. Our study demonstrates that transgenic expression of JAK2V617F is capable of producing all three phenotypes of MPNs in a transgense dose- and age-dependent manner. Our transgenic mice thus represent an excellent model system to study MPNs. Disclosures: No relevant conflicts of interest to declare.
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Doglio, Lynn, Joo Yeun Kim, Grazyna Bozek und Ursula Storb. „Expression ofλand K Genes Can Occur in all B Cells and is Initiated Around the Same Pre-B-Cell Developmental Stage“. Developmental Immunology 4, Nr. 1 (1994): 13–26. http://dx.doi.org/10.1155/1994/87352.
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Transgenic mice that carry a λ2 transgene under the control of the Vλ2 promoter and the Eλ2-4 enhancer (λ2Eλ mice) are described. A high proportion of B cells in the spleen and the bone marrow express the λ transgene on the cell membrane. λ2 protein is synthesized by all λ2Eλ-derived spleen B-cell hybridomas that have retained the transgene, suggesting that all B cells have the ability to express λ genes. Feedback inhibition of endogenous K-gene rearrangement is significant, but not complete. The results are similar to those with transgenic mice expressing the same λ2 transgene under the control of the heavy-chain enhancer (λ2EH mice). Although the λ2EH transgene is expressed before the λ2Eλ transgene, feedback inhibition seems to occur at about the same stage of B-cell development, regardless of the timing of expression of the λ transgenes. Apparently, feedback is not necessarily coincident with the assembly of a heavy-chain/light-chain complex in pre-B cells. Expression of λ in the normal fetal liver coincides with the expression of K; thus, it appears that λ-gene transcription is not delayed. The differential rearrangement of K and λ genes is discussed in the light of these findings.
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Moeller, Marcus J., Abdulsalam Soofi, Silja Sanden, Jürgen Floege, Wilhelm Kriz und Lawrence B. Holzman. „An efficient system for tissue-specific overexpression of transgenes in podocytes in vivo“. American Journal of Physiology-Renal Physiology 289, Nr. 2 (August 2005): F481—F488. http://dx.doi.org/10.1152/ajprenal.00332.2004.
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The utility of promoter fragments isolated from the 5′-flanking region of endogenous mammalian genes to drive transgene expression in vivo is often limited by low expression levels. In this study, a bigenic system was established that allows constitutive overexpression of transgenes in a tissue-specific fashion in transgenic mice in a time- and cost-effective fashion. A modified floxed expression vector was constructed [CMVflox-enhanced green fluorescent protein (eGFP)], in which a lacZ cassette (β-galactosidase) flanked by lox sites was placed between a CMV-promoter and the transgene of interest (eGFP). Before Cre recombination, expression of eGFP was effectively prevented by the interposed floxed lacZ cassette, whereas β-galactosidase was strongly expressed in transiently transfected cells. Transcription of the gene of interest (eGFP) could be irreversibly activated by cotransfection with Cre recombinase. Mice transgenic for CMVflox-eGFP were generated by pronuclear injection. A rapid assay was developed to identify transgenic founders with active transgene expression by measuring transgene activity (β-galactosidase) in tail biopsies. Transgene activity in tails correlated with transgene expression in most other tissues tested including podocytes within the kidney. To activate expression of the gene of interest in a tissue-specific fashion, founder mice were mated to the Cre mouse line 2.5P-Cre previously shown to mediate 100% Cre recombination exclusively in podocytes (Moeller MJ, Sanden SK, Soofi A, Wiggins RC, and Holzman LB. Genesis 35: 39–42, 2003). In doubly transgenic offspring, high-level eGFP expression resulting from Cre excision of the interposed lacZ cassette was detected in four of seven CMVflox-eGFP founder lines. This approach should also circumvent common limitations arising from lethality or transgene silencing as a consequence of transgene overexpression.