A transgenic mouse model for studying differentiation programs and lineage relationships in the developing mouse pulmonary epithelium.
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Animals↗
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New insights into insulin dependent diabetes mellitus from studies with transgenic mouse models.
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Animals↗
Studies on the immunogenicity of hCEA in a transgenic mouse model.
BACKGROUND AND AIMS: Immunization protocols in mice have shown that the tumor-associated antigen hCEA could be a target for active immunization; however, human CEA is foreign to mice. Success may depend in part on a simple anti-xenoresponse. Using hCEA-transfected syngeneic tumor cells in hCEA-transgenic mice should bypass this problem and allow testing for new vaccination strategies. MATERIALS AND METHODS: We established a hCEA transgenic model of the haplotype H2(d), which may differ from other haplotypes in cytokine production and in effectiveness of antigen presentation, and tested two vaccination protocols in wild-type and transgenic mice. RESULTS: Syngeneic wild-type mice built up an immune response with high antibody titers; only 65% of animals developed solid tumors after tumor challenge. In contrast, hCEA-transgenic mice developed no antibody response and accepted the tumor in more than 90% of cases, thus demonstrating the role of human CEA as a foreign antigen. Accordingly, active immunization using tumor lysate or lymphocytes loaded with hCEA resulted in a CTL response and tumor-rejection in up to 80% of wild-type mice. hCEA-transgenic mice could be induced with both immunization protocols to build up a CTL response, although the number of CTL were much lower and the cytotoxic response weaker than in wild-type mice. In vivo hCEA-transgenic mice rejected hCEA-positive tumors only after immunization with the tumor lysate in about 60% whereas there was no rejection of tumors after immunization with the human hCEA-loaded autologous lymphocytes. CONCLUSION: The findings clearly show the importance of transgenic models when testing the effects of immunization towards human tumor associated antigens such as hCEA because results differ in wild-type and transgenic mice.
Animals↗
Grg1 acts as a lung-specific oncogene in a transgenic mouse model.
Groucho proteins are transcriptional corepressors that are recruited to gene regulatory regions by numerous transcription factors. Long isoforms, such as Grg1, have all the domains of the prototype Drosophila Groucho. Short Groucho proteins, such as Grg5, have only the amino-terminal Q and G/P domains. We generated Grg1 and Grg5 transgenic mice and found that Grg1 overexpression induces lung adenocarcinoma, whereas Grg5 overexpression does not. Coexpression of Grg5 with Grg1 reduces tumor burden. Grg1 and Grg5 both diminish p53 protein levels; however, only Grg1 overexpression induces elevated levels of ErbB1 and ErbB2 receptor tyrosine kinases. The molecular and biological changes that accompany tumor progression in Grg1 transgenic mice closely reiterate events seen in human lung cancer. We also found that within a human lung tumor tissue array, a significant number of carcinomas overexpress Grg1/TLE1. Our data suggest that Grg1 overexpression contributes to malignancy in human lung cancers.
Adenocarcinoma↗
Aberrant stress response associated with severe hypoglycemia in a transgenic mouse model of Alzheimer's disease.
Patients with Alzheimer's disease (AD) exhibit alterations in glucose metabolism and dysregulation of the stress-responsive hypothalamic-pituitary-adrenal (HPA) neuroendocrine system. The mechanisms responsible for these alterations and their possible contributions to the neurodegenerative process in AD are unknown. We now report that transgenic mice expressing a mutant form of human amyloid precursor protein (APP) that causes inherited early-onset AD exhibit increased sensitivity to physiological stressors, which is associated with aberrancies in HPA function and regulation of blood glucose levels. Specifically, APP mutant mice exhibit severe hypoglycemia and death following food restriction, and sustained elevations of plasma glucocorticoid levels and hypoglycemia following restraint stress. The alterations in HPA function and glucose regulation were evident in relatively young mice prior to overt deposition of amyloid beta-peptide (A beta). However, diffuse accumulations of A beta were present in the hypothalamus of older mice, suggesting a role for soluble forms of A beta in dysregulation of HPA function. Our data demonstrate disturbances in neuroendocrine function in APP mutant mice similar to those seen in AD patients. These impairments in stress response, glucocorticoid signaling, and regulation of blood glucose should be considered in interpretations of data from past and future studies of APP mutant mice.
Alzheimer Disease↗
Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis.
Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known how TBI contributes to the onset or progression of this common late life dementia. To address this question, we studied neuropathological and behavioral consequences of single versus repetitive mild TBI (mTBI) in transgenic (Tg) mice (Tg2576) that express mutant human Abeta precursor protein, and we demonstrate elevated brain Abeta levels and increased Abeta deposition. Nine-month-old Tg2576 and wild-type mice were subjected to single (n = 15) or repetitive (n = 39) mTBI or sham treatment (n = 37). At 2 d and 9 and 16 weeks after treatment, we assessed brain Abeta deposits and levels in addition to brain and urine isoprostanes generated by lipid peroxidation in these mice. A subset of mice also was studied behaviorally at 16 weeks after injury. Repetitive but not single mTBI increased Abeta deposition as well as levels of Abeta and isoprostanes only in Tg mice, and repetitive mTBI alone induced cognitive impairments but no motor deficits in these mice. This is the first experimental evidence linking TBI to mechanisms of AD by showing that repetitive TBI accelerates brain Abeta accumulation and oxidative stress, which we suggest could work synergistically to promote the onset or drive the progression of AD. Additional insights into the role of TBI in mechanisms of AD pathobiology could lead to strategies for reducing the risk of AD associated with previous episodes of brain trauma and for preventing progressive brain amyloidosis in AD patients.
Alzheimer Disease↗
Mucosal IL-7-mediated immune responses in chronic colitis-IL-7 transgenic mouse model.
We have demonstrated that intestinal epithelial cells produce interleukin-7 (IL-7) and IL-7 serves as a regulatory factor for proliferation of mucosal lymphocytes. To clarify the mechanism by which locally produced IL-7 regulates mucosal lymphocytes and the role of mucosal IL-7 in colonic inflammation, we investigated IL-7 transgenic (IL-7 Tg) mice and demonstrated that IL-7 Tg mice developed acute and chronic colitis with histopathological similarity to ulcerative colitis in humans. In concert with our recent findings that IL-7 stimulates the proliferation of inactivated mucosal lymphocytes but eliminates activated lymphocytes in the inflamed mucosa of human ulcerative colitis. These findings suggest that chronic inflammation in the colonic mucosa is mediated by dysregulation of epithelial cell-derived IL-7 system.
Animals↗
Transgenic mouse models for Alzheimer's disease: the role of GSK-3B in combined amyloid and tau-pathology.
Describing and understanding the pathological processes which devastate the brain of Alzheimer's disease (AD) patients remains a major target for experimental biology. We approached this problem by generating different types of single and double transgenic mice that develop pathological hallmarks of AD. In APP-V717 mice, the progression from intracellular amyloid to diffuse and senile plaques with vascular deposits, is preceded by early defects in cognition and LTP. In Tau-P301L mice, the morbid tauopathy with intracellular filaments, cause mortality before age 1 year. Ageing APP-V717IxTau-P301L double tg mice (14-17 months) have combined AD-like pathology in hippocampus and cortex consisting of amyloid plaques and neurofibrillary tangles. Remarkably, while Tau-P301L mice die before age 1 year, the APP-V717IxTau-P301L double tg mice survive much longer, which correlates with alleviation of tauopathy in hindbrain, despite aggravation in forebrain. This hypothesis is corroborated in Tau-P301LxGSK-3B double transgenic mice, which have also an extended lifespan relative to Tau-P301L mice, that correlates with reduction of brainstem tauopathy. At the same time, Tau-P301LxGSK-3B mice have dramatic forebrain tauopathy, with "tangles in almost all neurons", although without hyper-phosphorylation of Tau. The data corroborate the hypothesis that GSK-3B is the missing link between the amyloid and tau-pathology, and position GSK-3B as prominent player in the pathogenesis in AD.
Aging↗
Oral immunization with HCV-NS3-transformed Salmonella: induction of HCV-specific CTL in a transgenic mouse model.
BACKGROUND & AIMS: The ability to induce cytotoxic T cells is considered an important feature of a candidate hepatitis C virus (HCV) vaccine. We used an oral immunization strategy with attenuated HCV-NS3-transformed Salmonella typhimurium to deliver DNA directly to the gut-associated lymphoid tissue. METHODS: HLA-A2.1 transgenic mice were immunized once with transformed attenuated Salmonella. HCV-specific CD8+ T cells were analyzed in vitro as well as in vivo by challenge of mice with recombinant HCV-NS3 vaccinia virus. RESULTS: Salmonella (10(8) colony-forming units; 20 microg plasmid DNA) induced cytotoxic and IFN-gamma-producing CD8+ T cells specific for the immunodominant epitope NS3-1073 in 26 of 30 mice (86%) that persisted for at least 10 months. A second epitope (NS3-1169) was also recognized by cytotoxic and IFN-gamma-producing T cells, whereas a third one (NS3-1406) stimulated IFN-gamma production without cytotoxicity. The minimal amount of plasmid DNA required to induce CTLs was 2 ng. Upon challenge with recombinant HCV-NS3-expressing vaccinia virus, vaccinia titers were significantly lower in mice immunized with Salmonella-NS3 than in mice immunized with control Salmonella, demonstrating the in vivo function of CTLs. CONCLUSIONS: Oral immunization with attenuated Salmonella typhimurium as a carrier for HCV DNA induces long-lasting T-cell responses.
Administration, Oral↗
Recognition of HLA-B27 by mouse cytotoxic T-cell clones: a transgenic mouse model.
As a basis for the characterization of mouse T cells involved in the recognition of xenogeneic HLA molecules, a panel of HLA-B27-reactive cytotoxic T-cell clones was generated upon stimulation by cells from HLA-B27-transgenic mice. The HLA-B27-induced T-cell response was found to comprise two categories of clones: some recognizing HLA-B27 independent of H-2 molecules expressed by the target cells (unrestricted clones), others recognizing HLA-B27 in an H-2-restricted manner. The unrestricted clones exhibited diverse specificities, as judged from their various cross-reactivities with other xenogeneic (HLA) or allogeneic (H-2) molecules. In addition, although most of the unrestricted clones were able to react with both mouse and human HLA-B27-transgenic mice. The HLA-B27-induced T-cell which reacted only with HLA-B27-positive mouse, and not human cells. These findings illustrate that both H-2-restricted and unrestricted T cells with diverse specificities contribute to HLA-B27-xenorecognition.
Animals↗
Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model.
Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP-1 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/ enhancer. A model of CCl(4)-induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 itself did not induce liver fibrosis. There were no significant differences of pro-(alpha1)-collagen-I, (alpha2)-collagen-IV, and alpha-smooth muscle actin (alpha-SMA) mRNA expression in the liver between TIMP-Tg and Cont-mice, suggesting that overexpression of TIMP-1 itself did not cause hepatic stellate cell (HSC) activation. After 4-week treatment with CCl(4), however, densitometric analysis revealed that TIMP-Tg-mice had a seven-fold increase in liver fibrosis compared with the Cont-mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP-Tg-mice, whereas CCl(4)-induced liver dysfunction was not altered. An active form of matrix metalloproteinases-2 (MMP-2) level in the liver of TIMP-Tg-mice was decreased relative to that in Cont-mice because of the transgenic TIMP-1. Immunohistochemical analysis revealed that collagen-I and collagen-IV accumulation was markedly increased in the liver of CCl(4)-treated TIMP-Tg-mice with a pattern similar to that of alpha-SMA positive cells. These results suggest that TIMP-1 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development.
Actins↗
Role of apoE/Abeta interactions in Alzheimer's disease: insights from transgenic mouse models.
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Alzheimer Disease↗
Transgenic mouse models for the identification of human carcinogens: a European perspective.
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Animals↗
Asynchronous expression of myeloid antigens in leukemic cells in a PML/RARalpha transgenic mouse model.
Acute promyelocytic leukemia (APL) is characterized by the expansion of blasts that resemble morphologically promyelocytes and harbor a chromosomal translocation involving the retinoic acid receptor alpha (RARalpha) and the promyelocytic leukemia (PML) genes on chromosomes 17 and 15, respectively. The expression of the PML/RARalpha fusion gene is essential for APL genesis. In fact, transgenic mice (TM) expressing PML/RARalpha develop a form of leukemia that mimics the hematological findings of human APL. Leukemia is diagnosed after a long latency (approximately 12 months) during which no hematological abnormality is detected in peripheral blood (pre-leukemic phase). In humans, immunophenotypic analysis of APL blasts revealed distinct features; however, the precise immunophenotype of leukemic cells in the TM model has not been established. Our aim was to characterize the expression of myeloid antigens by leukemic cells from hCG-PML/RARalpha TM. In this study, TM (N = 12) developed leukemia at the mean age of 13.1 months. Morphological analysis of bone marrow revealed an increase of the percentage of immature myeloid cells in leukemic TM compared to pre-leukemic TM and wild-type controls (48.63 +/- 16.68, 10.83 +/- 8.11, 7.4 +/- 5.46%, respectively; P < 0.05). Flow cytometry analysis of bone marrow and spleen from leukemic TM identified the asynchronous co-expression of CD34, CD117, and CD11b. This abnormal phenotype was rarely detected prior to the diagnosis of leukemia and was present at similar frequencies in hematologically normal TM and wild-type controls of different ages. The present results demonstrate that, similarly to human APL, leukemic cells from hCG-PML/RARalpha TM present a specific immunophenotype.
Animals↗
Dramatic, expansion-biased, age-dependent, tissue-specific somatic mosaicism in a transgenic mouse model of triplet repeat instability.
Myotonic dystrophy type 1 (DM1) is one of a growing number of inherited human diseases whose molecular basis has been implicated as the expansion of a trinucleotide DNA repeat. Expanded disease-associated alleles of >50 CTG repeats are unstable in both the germline and soma. Expansion of the unstable alleles over time and variation of the level of mutation between the somatic tissues of an individual are thought to account at least partially for the tissue specificity and progressive nature of the symptoms. We previously generated a number of transgenic mouse lines containing a large expanded CTG repeat tract that replicated a number of the features of unstable DNA in humans, including frequent sex-specific changes in allele length during intergenerational transmission. Small length change mutations were apparent in the somatic tissues of young mice in all of the lines generated, but the gross instability observed in human DM1 patients was not replicated. We now show that in one of the lines, Dmt -D, spectacular, expansion-biased, tissue-specific instability is observed in older mice. The highest levels of instability were detected in kidney with gains of >500 repeats, representing a tripling of allele length, in some cells. Mosaicism accumulated in an age-dependent manner, but the tissue specificity did not obviously correlate with cell turnover. Such gross somatic mosaicism was not observed in three other lines examined, further emphasizing a role for flanking DNA in modulating repeat stability.
Age Factors↗
Formation of intermediate filament protein aggregates with disparate effects in two transgenic mouse models lacking the neurofilament light subunit.
Protein aggregates containing intermediate filaments (IFs) are a hallmark of degenerating spinal motor neurons in amyotrophic lateral sclerosis (ALS). Recently, we reported that a deficiency in neurofilament light subunit (NF-L), a phenomenon associated with ALS, promoted the formation of IF inclusions with ensuing motor neuron death in transgenic mice overproducing peripherin, a type III IF protein detected in axonal inclusions of ALS patients. To further assess the role of NF-L in the formation of abnormal IF inclusions, we generated transgenic mice overexpressing human neurofilament heavy subunits (hNF-H) in a context of targeted disruption of the NF-L gene (hH;L-/- mice). The hH;L-/- mice exhibited motor dysfunction, and they developed nonfilamentous protein aggregates containing NF-H and peripherin proteins in the perikarya of spinal motor neurons. However, the perikaryal protein aggregates in the hH;L-/- mice did not provoke motor neuron death, unlike toxic IF inclusions induced by peripherin overexpression in NF-L null mice (Per;L-/- mice). Our results indicate that different types of IF protein aggregates with distinct properties may occur in a context of NF-L deficiency and that an axonal localization of such aggregates may be an important factor of toxicity.
Animals↗
Alpha-1-antichymotrypsin promotes beta-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer's disease.
Alpha(1)-antichymotrypsin (ACT), an acute-phase inflammatory protein, is an integral component of the amyloid deposits in Alzheimer's disease (AD) and has been shown to catalyze amyloid beta-peptide polymerization in vitro. We have investigated the impact of ACT on amyloid deposition in vivo by generating transgenic GFAP-ACT-expressing mice and crossing them with the PDGF-hAPP/V717F mice, which deposit amyloid in an age-dependent manner. The number of amyloid deposits measured by Congo Red birefringence was increased in the double ACT/amyloid precursor protein (APP) transgenic mice compared with transgenic mice that only expressed APP, particularly in the hippocampus where ACT expression was highest, and the increase was preceded by elevated total amyloid beta-peptide levels at an early age. Our data demonstrate that ACT promotes amyloid deposition and provide a specific mechanism by which inflammation and the subsequent upregulation of astrocytic ACT expression in AD brain contributes to AD pathogenesis.
Alzheimer Disease↗
Transgenic mouse model for echovirus myocarditis and paralysis.
Echoviruses have been implicated in multiple human disease syndromes, including aseptic meningitis, paralysis, and heart disease, but no animal model is available for studying the pathogenesis of infection. Production of human integrin very late antigen 2, a receptor for echovirus type 1, in transgenic mice conferred susceptibility to viral infection. Intracerebral inoculation of newborn transgenic mice with echovirus leads to paralysis and wasting. No disease was observed in infected nontransgenic mice. In paralyzed mice significant damage was observed in the outer layers of the cerebrum, and numerous condensed neuronal nuclei were present. In contrast, intracerebral inoculation of adolescent (3- to 4-week-old) transgenic mice with echovirus type 1 did not lead to paralysis but an acute wasting phenotype and myocarditis. These findings establish human very late antigen 2 transgenic mice as a model for echovirus pathogenesis.
Aging↗