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PubMed1992

Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease.

The effect of mammary gland-specific expression of the polyomavirus middle T antigen was examined by establishing lines of transgenic mice that carry the middle T oncogene under the transcriptional control of the mouse mammary tumor virus promoter/enhancer. By contrast to most transgenic strains carrying activated oncogenes, expression of polyomavirus middle T antigen resulted in the widespread transformation of the mammary epithelium and the rapid production of multifocal mammary adenocarcinomas. Interestingly, the majority of the tumor-bearing transgenic mice developed secondary metastatic tumors in the lung. Taken together, these results suggest that middle T antigen acts as a potent oncogene in the mammary epithelium and that cells that express it possess an enhanced metastatic potential.

Animals↗
PubMed2000

Alzheimer's disease: transgenic mouse models and drug assessment.

Alzheimer's disease (AD), characterized by neuritic plaques and neurofibrillary tangles of the brain, is experienced by more and more elderly people in a form of senile dementia. Four genes are closely linked with AD and are located on chromosomes 21, 19, 14 and 1. Transgenic technology enables the development of animal models for research into this human disease. Recently reported transgenic AD mouse models, which express AD-related mutant human genes, develop some significant aspects of AD-like pathology. The specific role of these mice in representing different targets, the consequent pathology of AD and the availability of this increasingly popular tool for investigating new therapeutic strategies for AD are reviewed.

Alzheimer Disease↗
PubMed2002

Cellular cardiomyoplasty in a transgenic mouse model.

BACKGROUND: Recent progress in the cardiotypic differentiation of embryonic and somatic stem cells opens novel prospects for the treatment of cardiovascular disorders. The aim of the present study was to develop a novel surgical approach that allows standardized cellular cardiomyoplasty in mouse with low-perioperative mortality. METHODS: Reproducible transmural lesions were generated by cryoinjury followed by intramural injection of embryonic cardiomyocytes using a newly designed holding device and vital dye staining. This approach was validated with a transgenic mouse model, in which the live reporter gene-enhanced green fluorescent protein (EGFP) is under control of a cardiac-specific promoter. RESULTS: The perioperative mortality was 10%. The engrafted EGFP-positive cardiomyocytes could be identified in a high percentage (72.2%, n=36) of operated animals. CONCLUSIONS: This novel approach enables reliable cellular replacement therapy in mouse and greatly facilitates the analysis of its molecular, cellular, and functional efficacy.

Animals↗
PubMed2006

MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease.

MAPK-activated protein kinase 2 (MAPKAP K2 or MK2) is one of several kinases directly regulated by p38 MAPK. A role for p38 MAPK in the pathology of Alzheimer disease (AD) has previously been suggested. Here, we provide evidence to suggest that MK2 also plays a role in neuroinflammatory and neurodegenerative pathology of relevance to AD. MK2 activation and expression were increased in lipopolysaccharide (LPS) + interferon gamma-stimulated microglial cells, implicating a role for MK2 in eliciting a pro-inflammatory response. Microglia cultured ex vivo from MK2-deficient (MK2-/-) mice demonstrated significant inhibition in release of tumor necrosis factor alpha, KC (mouse chemokine with highest sequence identity to human GROs and interleukin-8), and macrophage inflammatory protein 1alpha on stimulation with LPS + interferon gamma or amyloid-beta peptide (1-42) compared with MK2+/+ wild-type microglia. Consistent with an inhibition in pro-inflammatory mediator release, cortical neurons co-cultured with LPS + interferon gamma-stimulated or amyloid-beta peptide (1-42)-stimulated MK2-/- microglia were protected from microglial-mediated neuronal cell toxicity. In a transgenic mouse model of AD in which amyloid precursor protein and presenilin-1 harboring familial AD mutations are overexpressed in specific regions of the brain, elevated activation and expression of MK2 correlated with beta-amyloid deposition, microglial activation, and up-regulation of tumor necrosis factor alpha, macrophage inflammatory protein 1alpha, and KC gene expression in the same brain regions. Our data propose a role for MK2 in AD brain pathology, for which neuroinflammation involving cytokines and chemokines and overt neuronal loss have been documented.

Alzheimer Disease↗
PubMed2006

Fluoro-Jade B staining as useful tool to identify activated microglia and astrocytes in a mouse transgenic model of Alzheimer's disease.

Fluoro-Jade B is known as a high affinity fluorescent marker for the localization of neuronal degeneration during acute neuronal distress. However, one study suggested that fluoro-Jade B stains reactive astroglia in the primate cerebral cortex. In this study, we analyzed the staining of fluoro-Jade B alone or combined with specific markers for detection of glial fibrillary acidic protein (GFAP) or activated CD68 microglia in the double APP(SL)/PS1 KI transgenic mice of Alzheimer's disease (AD), which display a massive neuronal loss in the CA1 region of the hippocampus. Our results showed that fluoro-Jade B did not stain normal and degenerating neurons in this double mouse transgenic model. Fluoro-Jade B was co-localized with Abeta in the core of amyloid deposits and in glia-like cells expressing Abeta. Furthermore, fluoro-Jade B was co-localized with CD68/macrosialin, a specific marker of activated microglia, and with GFAP for astrocytes in APP(SL)/PS1 KI transgenic mice of AD. Taken together, these findings showed that fluoro-Jade B can be used to label activated microglia and astrocytes which are abundant in the brain of these AD transgenic mice. It could stain degenerating neurons as a result of acute insult while it could label activated microglia and astrocytes during a chronic neuronal degenerative process such as AD for example.

Age Factors↗
PubMed2002

Differential expression patterns of matrix metalloproteinases and their inhibitors during development of osteoarthritis in a transgenic mouse model.

OBJECTIVE: To characterise the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) during degeneration of articular cartilage in a transgenic Del1 mouse model for osteoarthritis. METHODS: Northern analysis was used to measure mRNA levels of MMP-2, -3, -8, -9, -13, and -14, and TIMP-1, -2, and -3 in total RNA extracted from knee joints of transgenic Del1 mice, harbouring a 15 amino acid deletion in the triple helical domain of the alpha1(II) collagen chain, using their non-transgenic littermates as controls. Immunohistochemistry was used to study the presence of cleavage products (neoepitopes) of type II collagen, and the distribution of MMP-13 and TIMP-1 in degenerating cartilage. RESULTS: Each of the MMP and TIMP mRNAs analysed exhibited distinct expression patterns during development and osteoarthritic degeneration of the knee joint. The most striking change was up regulation of MMP-13 mRNA expression in the knee joints of Del1 mice at the onset of cartilage degeneration. However, the strongest immunostaining for MMP-13 and its inhibitor TIMP-1 was not seen in the degenerating articular cartilage but in synovial tissue, deep calcified cartilage, and subchondral bone. The localisation of type II collagen neoepitopes in chondrocytes and their pericellular matrix followed a similar pattern; they were not seen in cartilage fibrillations, but in adjacent unaffected cartilage. CONCLUSION: The primary localisation of MMP-13 and TIMP-1 in hyperplastic synovial tissue, subchondral bone, and calcified cartilage suggests that up regulation of MMP-13 expression during early degeneration of articular cartilage is a secondary response to cartilage erosion. This interpretation is supported by the distribution of type II collagen neoepitopes. Synovial production of MMP-13 may be related to removal of tissue debris released from articular cartilage. In the deep calcified cartilage and adjacent subchondral bone, MMP-13 probably participates in tissue remodelling.

Animals↗
PubMed2004

Neurotransmitter receptor analysis in transgenic mouse models.

One of the characteristic findings in human Huntington's disease (HD) is the alteration of neurotransmitter receptors. To a remarkable degree, transgenic HD mouse models recapitulate neurotransmitter receptor alterations. Neurotransmitter receptors can be assessed at the protein level by using receptor-binding autoradiography. One can also measure levels of receptor messenger RNA with in situ hybridization (ISH), employing either oligonucleotide or ribonucleotide probes. Both of these techniques-receptor-binding autoradiography and in situ hybridization-yield quantitative and regionally specific information regarding neurotransmitter receptors. We describe techniques for performing receptor-binding autoradiography and two types of in situ hybridization using oligonucleotide and ribonucleotide probes. With receptor binding and ISH, one can obtain quantitative region-specific assessments of neurotransmitter receptor alteration, a key pathologic event in HD pathogenesis.

Animals↗
PubMed2005

Magnetic resonance imaging and characterization of spontaneous lesions in a transgenic mouse model of tuberous sclerosis as a model for endothelial cell-based transgene delivery.

Tuberous sclerosis (TSC) is an autosomal dominant genetic disorder characterized by abnormalities in cellular migration, proliferation, and differentiation in many tissues. Benign hamartomas develop in multiple organs, believed to be caused by somatic mutation in addition to germ line mutation to cause loss of both alleles of either the TSC1 or TSC2 tumor suppressor gene, with resultant dysregulated growth due to loss of hamartin or tuberin function, respectively. This study focuses on detecting spontaneous lesions in a knockout mouse model of TSC2 by magnetic resonance imaging (MRI) and exploring the efficiency of introducing gene products into lesions, using transduced endothelial cells as gene vehicles. MRI was shown to be effective in detecting spontaneous lesions in multiple tissues as a means of assessing the prevalence of tumors. Tsc(2+/) heterozygous mice were screened at 12-24 months of age. MRI detected 100% of the renal lesions (cystadenomas, renal cell carcinomas) and 75% of the hepatic lesions (hemangiosarcomas), later identified by histology. Cell-mediated gene delivery was evaluated by immunohistochemical analysis of renal, hepatic, and lung lesions after intravenous delivery of MS1 mouse endothelial cells, transduced to express an enhanced form of green fluorescent protein (EGFP). Preliminary immunohistochemical analysis, using a polyclonal antibody to EGFP and a horseradish peroxidase-diaminobenzidine detection system, revealed these cells throughout liver, kidney, and lung sections from injected animals, organs that are frequently affected in TSC2 patients, as well as within the lesions themselves.

Animals↗
PubMed2001

[Role of podocyte damage in the pathogenesis of glomerulosclerosis and tubulointerstitial lesions: findings in the growth hormone transgenic mouse model of progressive nephropathy].

The sequence of structural changes terminating in glomerulosclerosis, tubular atrophy and interstitial fibrosis was analyzed in the growth hormone (GH) transgenic mouse (TM) model of progressive renal disease. The investigation was performed in TM expressing the bovine GH gene under the control of the murine metallothionein-1-promoter and non-transgenic controls (CM) of different age groups. The kidneys were studied by light microscopy, transmission and scanning electron microscopy, and were analyzed with stereological methods. Early-stage renal lesions were characterized by glomerular hypertrophy and mesangial expansion. In 7-week-old TM the mean glomerular volume was twice that of age-matched CM. The number of endothelial and of mesangial cells per glomerulus was increased in TM vs. CM, while the number of podocytes did not change. The podocytes demonstrated hypertrophy and foot process effacement. Concomitant with an age-related further increase of glomerular size in TM, severe maladaptive podocyte lesions including detachment of podocytes were observed. The resultant denudation of the glomerular basement membrane was associated with severe proteinuria, glomerular hyalinosis, synechia formation and collapse of glomerular capillaries. These lesions progressed to glomerular obsolescence that was associated with atrophy of the adjacent tubule and interstitial fibrosis. The progressive kidney lesions in this model appear to be attributable to a considerable extent to podocyte damage resulting from the limited capacity of this cell type to keep up with progressing overall tuft growth. The findings provide further evidence that mature podocytes are unable for effective cell replication in vivo, and that podocyte damage plays a significant role in the pathogenesis of progressive glomerulosclerosis with tubular atrophy and interstitial fibrosis.

Animals↗
PubMed2006

Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation.

We describe a double-transgenic mouse strain (opticospinal EAE [OSE] mouse) that spontaneously develops an EAE-like neurological syndrome closely resembling a human variant of multiple sclerosis, Devic disease (also called neuromyelitis optica). Like in Devic disease, the inflammatory, demyelinating lesions were located in the optic nerve and spinal cord, sparing brain and cerebellum, and the murine lesions showed histological similarity with their human correlates. OSE mice have recombination-competent immune cells expressing a TCR-alphabeta specific for myelin oligodendrocyte glycoprotein (MOG) aa 35-55 peptide in the context of I-Ab along with an Ig J region replaced by the recombined heavy chain of a monoclonal antibody binding to a conformational epitope on MOG. OSE mouse B cells bound even high dilutions of recombinant MOG, but not MOG peptide, and processed and presented it to autologous T cells. In addition, in OSE mice, but not in single-transgenic parental mice, anti-MOG antibodies were switched from IgM to IgG1.

Animals↗
PubMed2002

Feasibility of using autologous transplantation to evaluate hematopoietic stem cell-based gene therapy strategies in transgenic mouse models of human disease.

Histoincompatibility between murine donors and recipients of bone marrow (BM) transplants reduces engraftment, and this compromises assessment of hematopoietic stem cells (HSCs) in certain transgenic mice. To study HSCs in the S+S-Antilles mouse model of human sickle cell disease (SCD), we developed an autotransplant protocol. Initial experiments showed no differences between S+S-Antilles mice and normal C57BL/6 (+/+) mice in their radiosensitivity or baseline hematopoietic progenitor numbers. The kinetics of red blood cell (RBC) replacement post-transplant in +/+ recipients of mixtures of transgenic and +/+ BM cells also showed no competitive advantage of the +/+ cells. BM cells were then aspirated from mice 4 days after 5-fluorouracil treatment, transduced with a green fluorescent protein (GFP)-encoding retrovirus, and transplanted into the same recipients that, just before transplant, were irradiated with 800 cGy. We subsequently detected high levels of GFP(+) RBCs (21-79%) and white blood cells (WBCs; 35-88%) in the blood for 11 months and showed that transduced HSCs regenerated in the primary mice also repopulated secondary mice. These findings provide a generally applicable protocol for performing autotransplants in mice and forecast the potential utility of this approach in assessing HSC-based gene therapy protocols in transgenic mouse models of many human diseases.

Anemia, Sickle Cell↗
PubMed1988

Behavioral and neurochemical evaluation of a transgenic mouse model of Lesch-Nyhan syndrome.

Two transgenic strains of mutant mice lacking hypoxanthine-guanidine phosphoribosyltransferase (HPRT) activity were examined behaviorally and neurochemically for phenotypic similarity to the human Lesch-Nyhan syndrome. In this syndrome, male children markedly deficient in the enzyme HPRT develop self-mutilation and severe motoric difficulties, and exhibit a pronounced deficiency of dopamine in the basal ganglia. The HPRT-deficient mice showed no evidence of self-mutilation, no detectable motor impairments on tests selected for sensitivity to basal ganglia dysfunction, and no differences in response to apomorphine. Biochemical analyses revealed significantly lower levels of striatal dopamine in the HPRT-deficient mice than in HPRT normal littermates, but the depletion was only of the order of 19%. The results suggest that mice lacking HPRT activity do not phenotypically resemble children born with the same enzymatic deficiency in part because mutant mouse striatal dopamine levels are not as low as those seen in clinical cases with Lesch-Nyhan disease. In contrast to Lesch-Nyhan children, mice may be able to utilize alternative pathways more effectively to maintain purine and neurotransmitter levels within the ranges required for normal brain development and function.

Animals↗
PubMed2002

Transgenic mouse models for studying the role of cartilage macromolecules in osteoarthritis.

The development of transgenic technology has made possible the generation of targeted gene-mutated mouse lines suitable for use in experimental osteoarthritis (OA) research. Transgenic mice harbouring mutations in cartilage collagen types II and IX develop early-onset OA and are therefore promising models of age-related OA, even though the mice often show signs of chondrodysplasia. Also, mouse lines harbouring other engineered mutations of the extracellular molecules have given rise to early OA. The molecular background of a few spontaneous mutations in mice has also been clarified and the characterization of the OA phenotype is now in progress. These mutations cause severe chondrodysplasia and death in homozygous mice, but the heterozygous offspring develop the early-onset OA phenotype.

Animals↗
PubMed2002

Conditional over-expression of estrogen receptor alpha in a transgenic mouse model.

Attempts to delineate the mechanisms of estrogen action have promoted the creation of several estrogen receptor alpha (ERalpha) mouse models in the past decade. These traditional models are limited by the fact that the receptors are either absent or present throughout all stages of development. The purpose of this work was to develop a conditional transgenic model that would provide an in vivo method of controlling the spatial and temporal regulation of ERalpha expression. The tetracycline responsive system was utilized. Three lines of transgenic mice carrying a transgene composed of the coding sequence for murine ERalpha placed under the regulatory control of a tet operator promoter (tet-op) were generated. These three lines of tet-op-mERa mice were each mated to an established line of transgenic mice expressing a tetracycline-dependent transactivator protein (tTA) from the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). Double transgenic MMTV-tTA/tet-op-mERalpha mice were produced. All three lines demonstrated dominant gain of ERalpha shown by RT-PCR, immunoprecipitation, and immunohistochemistry. Transgene-specific ERalpha was expressed in numerous tissues including the mammary gland, salivary gland, testis, seminal vesicle, and epididymis. Expression was silenced by administration of doxycycline in the drinking water. This model can be utilized to evaluate the consequences of ERalpha dominant gain in targeted tissues at specific times during development. In this study dominant gain of ERalpha was associated with a reduction in epididymal/vas deferens and seminal vesicle weights consistent with the proposed action of ERalpha on fluid transport in the male reproductive tract. Combining this model with other dominant gain and gene knockout mouse models will be useful for testing effects of ERalpha action in combination with specific gene products and to evaluate if developmental and stage-specific expression of ERalpha can rescue identified phenotypes in gene knockout mice.

Animals↗
PubMed2004

Castration restores function and neurofilament alterations of aged symptomatic males in a transgenic mouse model of spinal and bulbar muscular atrophy.

Transgenic models of neurodegenerative disease have proved uniquely powerful for delineating pathways of neuronal dysfunction and cell death. We have developed a transgenic model of the polyglutamine disease spinal and bulbar muscular atrophy (SBMA), an adult-onset, slowly progressive motor neuron disease caused by polyglutamine expansion in the androgen receptor (AR). Mice bearing a human AR with 112 glutamines reproduce many aspects of SBMA, including slowly progressive, gender-specific motor deficits, and neuronal intranuclear inclusions. Despite substantial motor deficits in male AR112Q mice, no motor neuron loss was observed, indicating that neuronal dysfunction, rather than neuronal death, is central to disease. Moreover, reduced levels of unphosphorylated neurofilament heavy chain (NF-H) were observed in motor neurons, suggesting a role for NF-H in SBMA neuronal dysfunction. The elimination of androgens by surgical castration of severely affected, aged 112Q male mice partially restored motor function as well as NF-H levels. These data suggest that hormone-based therapies designed to treat SBMA patients, even with advanced disease, are likely to be effective.

Animals↗
PubMed1998

Passive but not active CD8+ T cell-based immunotherapy interferes with liver tumor progression in a transgenic mouse model.

To evaluate tumor immunotherapies, we used transgenic mice that harbor a progressive liver tumor associated with the expression of the SV40 large tumor T oncoprotein (SV40-T). To induce "self" tumor Ag-specific CD8+ T cells, mice were injected with an immunodominant SV40-T CTL epitope mixed with a heterologous helper peptide. Despite repeated injections, this vaccine failed to raise a tumor-specific CD8+ T cell response that was efficient enough to counteract tumors. Although coimmunization with SV40-T CTL epitope and heterologous helper peptide efficiently recruited the respective Th cells, only low-avidity SV40-T-specific CD8+ T cells were activated. Furthermore, major alterations in SV40-T-specific B and Th cell responses were characterized. In contrast, transfers of higher-avidity CTLs specific for the same SV40-T epitope were effective in counteracting tumors. These results suggest that passive therapies targeted to self tumor Ag may be more suitable than active immunization in the treatment of spontaneous tumors.

Adoptive Transfer↗
PubMed2002

Poliovirus pathogenesis in a new poliovirus receptor transgenic mouse model: age-dependent paralysis and a mucosal route of infection.

We constructed a poliovirus receptor (PVR) transgenic mouse line carrying a PVR delta cDNA driven by a beta-actin promoter. We refer to this model as the cPVR mouse. The cPVR mice express Pvr in a variety of tissues (including small intestines, brain, spinal cord, muscle, blood and liver) and are susceptible to infection after intraperitoneal, intracerebral or intramuscular inoculation of poliovirus. After intraperitoneal inoculation, poliovirus replication is observed in cPVR muscle, brain, spinal cord and, notably, small intestine. The cPVR mice exhibit a striking age-dependent paralysis after intramuscular infection, with 2-week-old mice being 10,000-fold more susceptible to paralytic disease than adult mice. The cPVR mice are also susceptible to paralysis following intranasal infection with poliovirus. After intranasal infection, virus replication is observed in the olfactory bulb, cerebrum, brain stem and spinal cord, suggesting that intranasal infection of cPVR mice is a model for bulbar paralysis. Intranasally infected mice frequently display unusual neurological behaviours. The PVR transgenic mouse reported here provides the first available model for a mucosal route of infection with poliovirus.

Age Factors↗
PubMed2004

Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease.

According to the "amyloid hypothesis of Alzheimer's disease," beta-amyloid is the primary driving force in Alzheimer's disease pathogenesis. Despite the development of many transgenic mouse lines developing abundant beta-amyloid-containing plaques in the brain, the actual link between amyloid plaques and neuron loss has not been clearly established, as reports on neuron loss in these models have remained controversial. We investigated transgenic mice expressing human mutant amyloid precursor protein APP751 (KM670/671NL and V717I) and human mutant presenilin-1 (PS-1 M146L). Stereologic and image analyses revealed substantial age-related neuron loss in the hippocampal pyramidal cell layer of APP/PS-1 double-transgenic mice. The loss of neurons was observed at sites of Abeta aggregation and surrounding astrocytes but, most importantly, was also clearly observed in areas of the parenchyma distant from plaques. These findings point to the potential involvement of more than one mechanism in hippocampal neuron loss in this APP/PS-1 double-transgenic mouse model of Alzheimer's disease.

Aging↗