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PubMed2006

Motor unit number estimation predicts disease onset and survival in a transgenic mouse model of amyotrophic lateral sclerosis.

Motor unit number estimation (MUNE) has proved useful in predicting rate of progression and survival in patients with amyotrophic lateral sclerosis (ALS). In animal models, it has demonstrated physiological effects of experimental medications that were not evident behaviorally. We sought to determine more specifically what aspects of function and survival that MUNE could predict in the G93A transgenic mouse model of ALS. Transgenic mice were examined in two distinct treatment studies, neither of which showed an effect of drug on survival, behavioral measures, or MUNE. MUNE was performed using a modification of the incremental stimulation method by stimulating the sciatic nerve at the sciatic notch, and recording with a circumferential surface electrode around the ipsilateral distal hindlimb. Both limbs were studied and the results averaged. MUNE was performed longitudinally on all animals from near onset to premorbid state. Each study was evaluated separately. For both studies, MUNE at initial study correlated significantly with behavioral determination of disease onset, and MUNE slope from initial to final study correlated significantly with disease duration, as measured from onset to time of death. However, the final MUNE value did not correlate with survival. Thus, in two studies involving animals with quite different disease courses, initial MUNE effectively predicted symptom onset and MUNE slope predicted survival. This suggests that MUNE has potential efficacy as a useful functional outcome measure in both animal and human studies of ALS.

Age of Onset↗
PubMed2003

Modulation of the JNK and p38 pathways by cdk5 protein kinase in a transgenic mouse model of Alzheimer's disease.

In this study we have used the transgenic mouse model Tg2576 to analyze the involvement of anomalous loss of regulation of cdk5 and the stress kinases JNK and p38 in brain neuronal death as related to neurodegenerative disorders such as Alzheimer's disease. Previous studies on hippocampal cells led us to the discovery that the cdk5/p35 complex is activated in neurodegeneration, a finding that was confirmed later in the transgenic mouse model. Here we show a link between the cdk5 system and JNK and p38 phosphoproteins, as an alternative pathway to neuronal death. Brains of the Tg2576 transgenic mice overexpressing amyloid precursor protein exhibited immunoreactivity with the phosphoproteins p-JNK, p-p38 and the GTPase protein Rac1 surrounding neuritic plaques. A significant increase in the immunodetection of JNK and p38 phosphoproteins in the Tg2576 mouse compared with wild type controls confirmed these findings. The significant increase in co-immunoprecipitation of p-JNK, p-p38 and Rac1 proteins with cdk5 in the transgenic mouse provided evidence for these interactions. At the cellular level, p-JNK and cdk5 colocalized in the cytoplasm of the cell bodies and neurites of brain cortical areas of the transgenic mouse. The present evidence suggests a cellular link between the cdk5 system and the stress kinase JNK and p38 pathways in an in vivo model. This study sheds new light on the pathogenesis of neuronal degeneration processes such as those occurring in Alzheimer's disease.

Alzheimer Disease↗
PubMed2003

A transgenic mouse model for the detailed morphological study of astrocytes.

We have generated a transgenic mouse model in which astrocytes express an enhanced green fluorescent protein (EGFP) under the control of the mouse glial fibrillary acidic protein (GFAP) promoter. EGFP, which is characteristically found throughout the cell, was expressed in these animals even in astrocytic fine processes, and EGFP expressing cells demonstrated morphological characters of protoplasmic, fibrous, or reactive astrocytes. In contrast, GFAP immunoreactivity was found only in the perinuclear region and in the main processes. The transgenic mouse model therefore provides a valuable tool for the detailed morphological investigation of astrocytes.

Animals↗
PubMed2001

Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta1 transgenic mouse model.

The pancreas morphology of transgenic mice that overexpress transforming growth factor-beta1 (TGF-beta1) in the pancreas resembles partially morphological features of chronic pancreatitis, such as progressive accumulation of extracellular matrix (ECM). Using this transgenic mouse model, we characterized the composition of pancreatic fibrosis and involved fibrogenic mediators. On day 14 after birth, fibrotic tissue was mainly composed of collagen type I and III. At this time, mRNA levels of TGF-beta1 were increased. On day 70, the ECM composition was expanded by increased deposition of fibronectin, whereas connective tissue growth factor, fibroblast growth factor (FGF)-1, and FGF-2 mRNA expression levels were elevated in addition to TGF-beta1. In parallel, the number of pancreatic stellate cells (PSC) increased over time. In vitro, TGF-beta1 stimulated collagen type I expression but not fibronectin expression in PSC, in contrast to FGF-2, which stimulated both. This confirms that TGF-beta1 mediates pancreatic fibrosis through activation of PSC and deposition of collagen type I and III at early time points. Furthermore, this points to an indirect mechanism in which TGF-beta regulates pancreatic ECM assembly by induction of additional growth factors.

Animals↗
PubMed2004

Effect of transgene copy number on survival in the G93A SOD1 transgenic mouse model of ALS.

Transgenic mice expressing multiple copies of the G93A mutant form of SOD1 develop motor neuron pathology and clinical symptoms similar to those seen in patients with amyotrophic lateral sclerosis (ALS). The phenotype of these mice is dependent on the number of transgene copies in their genome. Changes in transgene copy number, although rare, can sometimes occur while mating due to intra locus recombination events during meiosis. The objective of this study was to develop a real time quantitative PCR method to determine changes in transgene copy number in these mice and to evaluate the effect of transgene copy number on the phenotype of the G93A SOD1 mouse model of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1990

Transgenic mouse models of type I diabetes.

Transgenic mouse technology has gained recognition as an important tool for examining many fundamental biological questions in vivo. Recently, transgenic mouse techniques have been applied to the study of type I (insulin-dependent) diabetes. These studies have been particularly informative in elucidating 1) mechanisms whereby immune tolerance is maintained to antigens on rare specialized cells such as the pancreatic beta-cell, 2) disease susceptibility and resistance genes, and 3) potentially important immune effector mechanisms. In this article, we discuss these studies, their impact on understanding of the pathogenesis of type I diabetes, and the potential of the transgenic mouse approach for future research.

Animals↗
PubMed1996

Evaluation of a plasmid-based transgenic mouse model for detecting in vivo mutations.

To study in vivo somatic mutations a C57BL/6 transgenic mouse model was constructed harboring multiple chromosomally integrated copies of the plasmid pUR288, which carried the lacZ reporter gene as the mutational target. We previously demonstrated that lacZ-containing plasmids could be rescued from their integrated state efficient enough to detect mutations in lacZ by positive selection. The smaller size of the plasmid vector, as compared with our earlier transgenic mouse model based on bacteriophage lambda vectors, should offer considerable advantages in terms of rescue efficiency and sensitivity to large size alterations in the lacZ gene. To evaluate the plasmid-based mouse model for its suitability to detect in vivo mutations, we determined mutant frequencies in different organs of untreated and ethyl nitrosourea (ENU)-treated animals using a new, improved protocol. The rescue efficiencies obtained were as high as 200,000/micrograms genomic DNA; millions of transformants could be obtained in one single experiment. The average spontaneous mutant frequency in four different organs of 4- to 8-week-old mice ranged from 4.41 to 6.82 x 10(-5), compared with a mutant frequency of the same plasmid grown in Escherichia coli of approximately 1 x 10(-5) or less. Single treatments with 100 and 250 mg ENU/kg body wt resulted in a 7- and 14-fold increase, respectively, in spleen mutant frequency at 14 days after i.p. administration of the alkylating agent. Restriction enzyme analysis showed that a considerable portion of spontaneous mutants were size changes varying from approximately 100 to 3000 bp. Some mutant plasmids contained mouse genomic sequences, which is indicative of large genetic rearrangement events involving the 3' flanking regions of the transgene cluster. Among the ENU-induced mutants, size changes comprised only a minor fraction of the total, which is in keeping with the known ENU mutation spectra in vitro and in vivo. The high rescue efficiency of this plasmid-based model, in combination with its sensitivity to a broad spectrum of mutations, including large deletions, makes it very suitable as a general in vivo mutagenicity test system.

Animals↗
PubMed2005

Non-invasive imaging of a transgenic mouse model using a prostate-specific two-step transcriptional amplification strategy.

Non-invasive assessment of transgenic animals using bioluminescence imaging offers a rapid means of evaluating disease progression in animal models of disease. One of the challenges in the field is to develop models with robust expression to image repetitively live intact animals through solid tissues. The prostate-specific antigen (PSA) promoter is an attractive model for studying gene regulation due to its hormonal response and tissue-specificity permitting us to measure signaling events that occur within the native tissues. The use of the GAL4-VP16 activator offers a powerful means to augment gene expression levels driven by a weak promoter. We have used a two-step transcriptional amplification (TSTA) system to develop a transgenic mouse model to investigate the tissue-specificity and developmental regulation of firefly luciferase (fl) gene expression in living mice using bioluminescence imaging. We employed an enhanced prostate-specific promoter to drive the yeast transcriptional activator, GAL4-VP16 (effector). The reporter construct carries five Gal4 binding sites upstream of the fl gene. We generated a transgenic mouse model using a single vector carrying the effector and reporter constructs. The transgenic mice show prostate-specific expression as early as three weeks of age. The bioluminescence signal in the prostate is significantly higher than in other organs. We also demonstrate that blocking androgen availability can downregulate the fl expression in the prostate. The transgenic mice display normal physical characteristics and developmental behavior, indicating that the high level of GAL4 driven expression is well tolerated. These findings suggest that the GAL4-VP16 transactivator can be used to amplify reporter gene expression from a relatively weak promoter in a transgenic mouse model. The transgenic TSTA model in conjunction with other transgenic cancer models should also help to detect and track malignancies. The strategies developed will be useful for transgenic research in general by allowing for amplified tissue specific gene expression.

Animals↗
PubMed2005

Molecular characterization of salivary gland malignancy using the Smgb-Tag transgenic mouse model.

The molecular mechanisms underlying salivary gland tumorigenesis remain unclear. In order to identify genetic changes that occur during the development of invasive adenocarcinoma from normal salivary gland, we used the Smgb-Tag transgenic mouse model. This transgene induces the progressive development of dysplasia to invasive adenocarcinoma in the submandibular salivary gland. Gene expression patterns from 20 submandibular glands (two normal, nine dysplasia and nine adenocarcinoma samples) were assessed using a mouse 15 K cDNA array. Unsupervised hierarchical clustering was used to group gene expression based on 157 differentially expressed genes distinguishing between dysplasias and adenocarcinomas. Further analysis identified 25 significantly overexpressed and 28 underexpressed cDNA sequences in adenocarcinoma as compared to dysplasia. Differential expression of five genes (Lcn2, Ptn, Cd24a, Mapk6 and Rnps1) was validated by quantitative real-time RT-PCR in a total of 48 mouse salivary gland tissues (seven histologically normal, 13 dysplasias and 28 adenocarcinomas), including the 20 samples analyzed by cDNA arrays. Immunohistochemical analysis was used to validate the expression of Ptn and Cd24a at the protein level in a subset of 16 mouse salivary glands (four normal, five dysplasia and seven adenocarcinoma samples), as well as in 23 human submandibular gland tumors (16 pleomorphic adenomas, three adenoid cystic carcinomas, one acinic cell carcinoma, one adenocarcinoma NOS, one myoepithelial and one mucoepidermoid carcinoma). We thus demonstrated that the Smgb-Tag transgenic mouse model is a useful tool for the identification of genes that are deregulated in salivary gland adenocarcinomas. Our data suggest that Ptn and Cd24a may be genetic markers associated with salivary gland tumorigenesis and/or progression.

Adenocarcinoma↗
PubMed2006

CCL27 is a critical factor for the development of atopic dermatitis in the keratin-14 IL-4 transgenic mouse model.

The keratin-14 IL-4 transgenic (Tg) mouse model of atopic dermatitis (AD) is characterized by skin infiltration of T cells, early up-regulation of T(h)2 cytokines and late surge of T(h)1 cytokines. In the present study, we investigated the role of CCL27, a T cell skin-homing chemokine known to be elevated in sera of human AD patients, in disease development in our animal model of AD. The results showed that the mRNA and protein levels of CCL27 in the skin and serum were significantly increased in IL-4 Tg mice. The percentage of T cells expressing CCR10 in skin draining lymph nodes of IL-4 Tg mice was increased, consistent with the findings of >80% of skin-infiltrating T cells in Tg mice expressing CCR10. Chemotaxis transmigration assay demonstrated that CCL27 promotes a greater degree of migration of T cells in diseased Tg mice. Subcutaneous injection of neutralizing anti-CCL27 to IL-4 Tg mice with early skin lesions resulted in reduced clinical progression of inflammation, accompanied with decreased T cell and mast cell infiltration in the skin, and down-regulation of inflammatory cytokines. In conclusion, CCL27 and CCR10 interaction is important for the development of skin inflammation in our AD model.

Animals↗
PubMed1998

A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells.

A transgenic mouse model of metastatic prostate cancer has been developed that is 100% penetrant in multiple pedigrees. Nucleotides -6500 to +34 of the mouse cryptdin-2 gene were used to direct expression of simian virus 40 T antigen to a subset of neuroendocrine cells in all lobes of the FVB/N mouse prostate. Transgene expression is initiated between 7 and 8 weeks of age and leads to development of prostatic intraepithelial neoplasia within a week. Prostatic intraepithelial neoplasia progresses rapidly to local invasion. Metastases to lymph nodes, liver, lung, and bone are common by 6 months. Tumorigenesis is not dependent on androgens. This model indicates that the neuroendocrine cell lineage of the prostate is exquisitely sensitive to transformation and provides insights about the significance of neuroendocrine differentiation in human prostate cancer.

Animals↗
PubMed2006

High-resolution large-scale mosaic imaging using multiphoton microscopy to characterize transgenic mouse models of human neurological disorders.

The thorough characterization of transgenic mouse models of human central nervous system diseases is a necessary step in realizing the full benefit of using animal models to investigate disease processes and potential therapeutics. Because of the labor- and resource-intensive nature of high-resolution imaging, detailed investigation of possible structural or biochemical alterations in brain sections has typically focused on specific regions of interest as determined by the researcher a priori. For example, Parkinson's disease researchers often focus imaging on regions of the brain expected to exhibit pathology such as the substantia nigra and striatum. Because of limitations in acquiring and storing high-resolution imaging data, additional data contained in the specimen is not usually acquired or disseminated/reported to the research community. Here we present a method of imaging large regions of brain at close to the resolution limit of light microscopy using a mosaic imaging technique in conjunction with multiphoton microscopy. These maps are being used to characterize several genetically modified animal models of neurological disease by filling the information "gap" among techniques such as magnetic resonance imaging and electron microscopic analysis.

Animals↗
PubMedDate not supplied

Altered differentiation of hepatocytes in a transgenic mouse model of hepatocarcinogenesis.

Transgenic mice carrying the SV40 T antigen (TAg) gene, which develop hepatocellular and biliary cell tumors by 4 mo of age, show ductular structures in the neonatal liver. Coexpression of c-myc with TAg increases the extent and persistence of ductular lesions and also accelerates tumor development. To analyze possible links between altered gene expression and cell differentiation and to determine the relationship between the ductular structures and tumor development in these mice, ductular cells in single (TAg) and bitransgenic (TAg x c-myc) mice were characterized for biliary and hepatocellular differentiation, transgene expression, and proliferation activity. The results show that the ductular cells in these transgenic mice have characteristics of biliary cells, including basement membrane formation, positive laminin staining, and bile duct-specific lectin (Dolichos biflorus agglutinin and peanut agglutinin) binding, and characteristics of hepatocytes, including albumin expression and ultrastructural features such as round nuclei with 1 or 2 nucleoli and well-developed cytoplasmic organelles. However, differences in transgene expression and cell proliferation between the ductular cells and nonductular hepatocytes were not apparent. Thus, the ductular cells could not be defined as tumor progenitor cells in these mouse livers. However, this model suggests that manipulation of gene expression can alter differentiation of hepatic parenchymal cells.

Animals↗
PubMed1994

Evaluation of a transgenic mouse model for alpha-1-antitrypsin (AAT) related liver disease.

We have attempted to produce a transgenic mouse model of the neonatal liver disease associated with the human PIZ allele. Analysis of a number of transgenic mouse lines carrying either a normal human PIM gene construct or the mutant Z is reported. Using isoelectric focusing analysis of plasma from transgenic mice, we have shown that the human AAT proteins produced in mice are processed in a similar way to their counterparts in humans. By comparing the level of M and Z mRNA in liver with the levels of M and Z proteins in plasma we have inferred that, as in humans, the mutant protein tends to accumulate within the hepatocyte. Accumulation of Z protein has also been demonstrated by immunocytochemistry. Two of the M transgenic lines produce such high levels of the human protein that it, like the Z protein, accumulates as globules. Histological features of livers from 116 mice of different ages and genotypes were examined: 37 non-transgenic, 62 Z transgenic (23 low expressing and 39 high expressing) and 17 M transgenic mice, all high expressing. Cirrhosis or fibrosis was not seen in any animal and we were unable to find any evidence for neonatal liver disease. Some necrosis was seen in all genotypes and this increased significantly with age with one Z line showing significantly more frequent necrosis than any other group. This line, the highest expressing Z line, was back crossed onto 7 different genetic backgrounds but no major differences between the back crosses with respect to liver disease were observed. The mouse model we have developed is compared with other transgenic Z mouse models; none of these is representative of human neonatal liver disease. Our view is that the transgenic animals generated in these experiments may be most useful for investigating the liver manifestations that almost invariably occur in ZZ adults. Alteration of additional factors other than accumulation of Z protein, for example inactivation of the endogenous mouse genes or some environmental challenge, might produce a mouse model with more relevance to neonatal liver disease.

Animals↗
PubMed2000

Hemopoietic lineage commitment decisions: in vivo evidence from a transgenic mouse model harboring micro LCR-betapro-LacZ as a transgene.

A substantial body of published data suggests activation of lineage-specific genes in multipotential hemopoietic cells before their unilineage commitment. Because the behavior and plasticity of cells isolated in vitro away from microenvironmental constraints exercised in vivo may be altered, one wonders whether similar findings can be observed in a physiologic setting in vivo. We used a transgenic mouse model harboring human micro LCR together with beta promoter sequences as a transgene to examine activation of lineage-specific programs in vivo. By using LacZ as a reporter, we had the ability to detect, quantitate, and select live cells with different levels of LacZ activation. We found strong expression of LacZ by X-gal staining in 2 lineages-erythroid and megakaryocytic. Activation in the latter was a novel finding not previously observed when similar transgenes were used. We also found activation of muLCR-betapro at low levels in progenitor cells of granulocytic-macrophagic, erythroid, or megakaryocytic lineage detected by in vitro assays, suggesting activation before commitment to a specific lineage pathway. In particular, the expression of LacZ was graded among progenitors, so that in a proportion of them activation occurred only after commitment to erythroid or megakaryocytic lineage. In addition, we found quantitative reduction in LacZ expression between fetal liver and bone marrow-derived cells, the basis of which is unclear. Collectively our data provide in vivo evidence supporting the view that lineage-specific genes are expressed in a graded fashion in pluripotential cells before their irreversible unilineage commitment. (Blood. 2000;95:1274-1282)

Animals↗
PubMed2006

[Establishment of transgenic mouse model of familial amyotrophic lateral sclerosis and identification of the filial generation].

OBJECTIVE: To establish transgenic mouse models of familial amyotrophic lateral sclerosis (FALS) and identify the genotype of the first filial generation. METHODS: Six male B6SJL SOD1G93A/+ hemizygote mice were mated with 6 female B6SJLF1/J+/+ mice to produce the filial generation. The genomic DNA was extracted from the tail vein blood of the first filial generation mice and PCR was performed to amplify the hmSOD1 gene fragment. The genotype of the mice was determined by electrophoresis, and the PCR product was purified for further gene sequence analysis and detection of mutation loci. RESULTS: Fifty-three progeny mice were born and the survival rate before ALS onset was 98% (52/53), and among the survived mice, the positivity rate for hmSOD1 gene was 44.2% (23/52). Electrophoresis result showed that the PCR product of 236 bp was consistent with the hmSOD1 gene fragment, and the sequence of the PCR product was identical with hmSOD1 gene sequence of G93A mutant. CONCLUSION: Transgenic mouse models of ALS can be established in the first filial generation of male B6SJL SOD1G93A/+ mice mated with female B6SJLF1/J+/+. PCR technique can precisely identify the genotype of the filial generation.

Amyotrophic Lateral Sclerosis↗
PubMed2003

[Establishment of transgenic mouse models carrying human polymeric immunoglobulin receptor gene].

OBJECTIVE: To establish transgenic mouse models carrying human polymeric immunoglobulin receptor (pIgR) gene to render the mice prone to EBV infection in normal condition, thereby to facilitate the study of the role of Epstein-Barr virus (EBV) in the pathogenesis of nasopharyngeal carcinoma. METHOD: By means of microinjection, pIgR gene under the regulation by kerotinocyte-specific promoter ED-L2 was introduced into the pronuclei of mouse zygote, which was transferred into pseudo- pregnant female mice to induce nasopharynx-specific pIgR expression in the founder mice. RESULT: Six out of the 16 founder mice (37.5%) was tested by PCR to be pIgR-positive, while Southern blotting identified only 2 positive mice. CONCLUSION: Transgenic mice harboring pIgR gene can be used potentially as a new model for studying the pothogenesis of nasopharyngeal carcinoma by EBV.

Animals↗