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PubMed2000

Downregulation of the p53 tumor suppressor gene and upregulation of the bcl-2 gene in retinoic acid receptor alpha-deficient transgenic mice.

We recently demonstrated lymphoma development in transgenic mice deficient in retinoic acid receptor alpha (RARalpha). High incidence of lymphoma development in this transgenic mouse model system was similar to lymphoma development in p53 knockout mice. In an effort to understand the molecular basis of lymphomagenesis in RARalpha-deficient transgenic mice, we compared the levels of RARalpha to the levels of p53 mRNA, and Bcl-2, and Bax proteins in lymphoid and non-lymphoid tissues and in lymphomas derived from the RARalpha-deficient transgenic mice. The p53 mRNA levels were depleted in various tissues including spleen ( approximately 96%), thymus ( approximately 29%) and bone marrow ( approximately 62%) of RARalpha-deficient transgenic mice when compared with the normal littermates, and the reduction in p53 mRNA expression in the various tissues examined was proportional to the reduction in RARalpha expression. Bcl-2 to Bax ratios were highly increased in the lymphoid compartments (spleen >bone marrow >thymus) because of selective overexpression of Bcl-2 protein. In summary, RARalpha downmodulation in this transgenic mouse model system was accompanied by p53 downmodulation and deregulation of Bcl-2 to Bax ratios in the lymphoid compartments.

Animals↗
PubMed2001

Transgenic mice expressing bacterial phytase as a model for phosphorus pollution control.

We have developed transgenic mouse models to determine whether endogenous expression of phytase transgenes in the digestive tract of monogastric animals can increase the bioavailability of dietary phytate, a major but indigestible form of dietary phosphorus. We constructed phytase transgenes composed of the appA phytase gene from Escherichia coli regulated for expression in salivary glands by the rat R15 proline-rich protein promoter or by the mouse parotid secretory protein promoter. Transgenic phytase is highly expressed in the parotid salivary glands and secreted in saliva as an enzymatically active 55 kDa glycosylated protein. Expression of salivary phytase reduces fecal phosphorus by 11%. These results suggest that the introduction of salivary phytase transgenes into monogastric farm animals offers a promising biological approach to relieving the requirement for dietary phosphate supplements and to reducing phosphorus pollution from animal agriculture.

6-Phytase↗
PubMed1994

How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model.

We developed two distinct transgenic mouse models in which virus induced insulin-dependent (type 1) diabetes mellitus (IDDM). In one of these lines, the unique viral transgene was expressed in the islets of Langerhans and also in the thymus, but in the other line, expression was only in the islets. Insertion and expression of the viral (self) gene, per se, did not lead to IDDM, (incidence < 5%). By contrast, induction of an anti-self (anti-viral) CD8+ CTL response to the same virus later in life caused IDDM (incidence < 90%) in both transgenic lines, although the kinetics and requirements for CD4 help, the affinity and avidity of CD8+ CTL differed in each line. Mice not expressing the viral (self) gene in the thymus developed IDDM 10-14 days after infection. CD4+ T cells played no detectable role, since their depletion failed to alter either the kinetics or incidence of IDDM. By contrast, mice that expressed the viral gene in the thymus required significantly more time to develop IDDM. Their anti-self (viral) CD8+ CTL were of lower affinity and avidity than CD8+ CTL generated by nontransgenic controls. Disease was dependent on T cell help, since deletion of CD4+ cells completely circumvented the IDDM.

Animals↗
PubMed2004

Nilvadipine antagonizes both Abeta vasoactivity in isolated arteries, and the reduced cerebral blood flow in APPsw transgenic mice.

The development of Alzheimer's disease (AD) is generally thought to correlate with cerebral accumulation of Abeta. It has previously been shown that Abeta peptides enhance vasoconstriction in isolated arteries and oppose certain vasorelaxants. Moreover, exogenous application of Abeta peptides causes cerebral vasoconstriction in rodents and in transgenic mouse models of AD that overexpress Abeta there is reduced cerebral blood flow. In the present study, we investigated the effect of nilvadipine, a dihydropyridine-type calcium channel blocker, on Abeta induced vasoconstriction in isolated arteries and in vivo on cerebral blood flow (CBF) of an AD transgenic mouse model overexpressing Abeta (Tg APPsw line 2576). Nilvadipine completely inhibited the vasoactivity elicited by Abeta in rat aortae and in human middle cerebral arteries. The effect of a short treatment duration (2 weeks) with nilvadipine on regional CBF was investigated in 13-month-old Tg APPsw mice and control littermates using a laser Doppler imager. Additionally, CBF was also measured in 20-month-old Tg APPsw mice and control littermates that were chronically treated with nilvadipine for 7 months. Untreated Tg APPsw mice showed a reduction of regional CBF compared to their untreated control littermates. Nilvadipine restored cortical perfusion levels in Tg APPsw to values similar to those observed in control littermates without notably affecting the CBF of control mice. All together, these data suggest that nilvadipine might be useful for the treatment of oligemia associated with AD.

Aged↗
PubMed2000

Bcl-2 accelerates multistep prostate carcinogenesis in vivo.

The impact of bcl-2 proto-oncogene expression on the pathogenesis and progression of prostate cancer was examined in a transgenic mouse model. Probasin-bcl-2 transgenic mice were crossed with TRAMP (TRansgenic Adenocarcinoma Mouse Prostate) mice that express the SV40 early genes (T/t antigens) under probasin control. Prostate size, cell proliferation, apoptosis, and the incidence and latency of tumor formation were evaluated. The double transgenic, probasin-bcl-2 X TRAMP F1 (BxT) mice exhibited an increase in the wet weight of the prostate. This was associated with an increase in proliferation, attributable to T/t antigens, and a decrease in apoptosis attributable to bcl-2. The latency to tumor formation was also decreased in the BxT mice compared to the TRAMP mice. The incidence of metastases was identical in both the TRAMP and BxT mice. Lastly, the incidence of hormone-independent prostate cancer was reduced in the BxT mice compared to the TRAMP mice. Together, these results demonstrate that bcl-2 can facilitate multistep prostate carcinogenesis in vivo.

Adenocarcinoma↗
PubMed2004

Mouse models of infertility due to swollen spermatozoa.

Transgenic mice with male infertility, the c-ros knockout (KO) and GPX5-Tag2 transgenic mouse models, are compared. Both exhibit severely angulated sperm flagella explaining the infertility. As angulated spermatozoa are swollen cells, a failure in volume regulation is indicated. Differences between genotypes were also found: caudal spermatozoa from c-ros KO, but not GPX5-Tag2, could fertilise eggs in vitro; flagellar angulation occurred more within the epididymis of GPX5-Tag2 than c-ros KO mice; the osmotic pressure of cauda epididymidal fluid was lower only in GPX5-Tag2 mice; angulation of caudal sperm from c-ros KO, but not GPX5-Tag2 mice, decreased upon demembranation. These observations indicate that GPX5-Tag2 mice express an earlier, more severe defect. Gene chip analyses of the epididymides revealed decreased expression of the CRES (cystatin-related epididymal-spermatogenic) and MEP17 (murine epididymal protein 17) genes in both genotypes. Further analysis could pinpoint genes essential for epididymal regulation of sperm volume, explain infertility and suggest modes of male contraception.

Animals↗
PubMed2006

Dynamic posttranscriptional regulation of epsilon-globin gene expression in vivo.

Functional studies of embryonic epsilon-globin indicate that individuals with beta thalassemia or sickle cell disease are likely to benefit from therapeutic, transcriptional derepression of its encoding gene. The success of epsilon-globin gene-reactivation strategies, however, will be tempered by the stability that epsilon-globin mRNA exhibits in developmental stage-discordant definitive erythroid progenitors. Using cell culture and transgenic mouse model systems, we demonstrate that epsilon-globin mRNA is modestly unstable in immature, transcriptionally active erythroid cells, but that this characteristic has relatively little impact on the accumulation of epsilon-globin mRNA at subsequent stages of terminal differentiation. Importantly, the constitutive stability of epsilon-globin mRNA increases in transgenic mouse models of beta thalassemia, suggesting that epsilon- and beta-globin mRNAs are coregulated through a shared posttranscriptional mechanism. As anticipated, relevant cis-acting determinants of epsilon-globin mRNA stability map to its 3' UTR, consistent with the positioning of functionally related elements in other globin mRNAs. These studies demonstrate that posttranscriptional processes do not pose a significant practical barrier to epsilon-globin gene reactivation and, moreover, indicate that related therapeutic strategies may be particularly effective in individuals carrying beta-thalassemic gene defects.

Animals↗
PubMed2003

Use of genetically altered mice to study the role of serum amyloid P component in amyloid deposition.

A precise role for serum amyloid P component (SAP), a common component of all known types of amyloid fibrils, in amyloid deposition in vivo is not known. Thus we investigated the relationship between SAP and amyloid deposition, using the transgenic mouse model of familial amyloidotic polyneuropathy (FAP). Because high serum levels of mouse endogenous or human SAP did not affect human transthyretin-derived amyloid deporsition in the transgenic mouse model of FAP, we approached this question by analyzing the induction of experimental AA amyloidosis in SAP-deficient and wild-type mice. Our experiments presented compelling evidence that, although not essential in the deposition of AA amyloid, SAP significantly accelerates the reaction. We then examined the persistence of splenic AA amyloid fibrils in SAP-deficient and wild-type mice to assess potential ways of treating individuals with amyloidosis. Our results indicated that lack of SAP in AA amyloid deposits does not enhance regression of the deposits in vivo and suggested that dissociation of bound SAP from AA amyloid deposits would not significantly accelerate regression of the deposits in vivo.

Amyloid Neuropathies, Familial↗
PubMed2002

Hepatocarcinogenesis in hepatitis viral infection: lessons from transgenic mouse studies.

Over the past decade, genetically engineered mouse models have been used for studies of the mechanisms underlying human diseases. One advantage of these models is that the targeted protein executes its function in normal cells in their natural tissue microenvironments. Transgenic mouse models for human viral hepatitis have also been established and have provided new insights into the pathogenesis of hepatitis and hepatocellular carcinoma (HCC). In the search for the mechanism of hepatocarcinogenesis in hepatitis viral infection, two viral proteins, the core protein of hepatitis C virus (HCV) and the HBx protein of hepatitis B virus (HBV), have been shown to possess oncogenic potential through transgenic mouse studies, indicating the direct involvement of the hepatitis viruses in hepatocarcinogenesis. The presence of the hepatitis C virus core or HBx protein, which has an oncogenic potential, may allow some of the steps in multistep hepatocarcinogenesis to be skipped. This may explain the very high frequency of HCC in patients with HCV or HBV infection.

Animals↗
PubMed2006

Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice.

In parallel to imaging studies in humans with Alzheimer's disease (AD), we have mapped brain metabolic activity in transgenic mouse models of AD. Our aim in both is to provide new surrogate markers of progression to help clarify disease mechanisms and rapidly screen candidate therapeutics. Since previous findings of preferential reductions in posterior cingulate glucose metabolism may have been confounded by morphological abnormalities in previously studied "PDAPP" transgenic mice, we first assessed hippocampal and callosal anatomy in PSAPP (PS1xAPP) mice, another transgenic mouse model of AD, and found no major abnormalities. We then used fluorodeoxyglucose (FDG) autoradiography in older and younger PSAPP and wildtype mice to assess the functional state of 56 regions-of-interest across group, age and increasing amyloid load. Reductions in FDG uptake in aged transgenic mice, with significant interactions between group and age, were found in retrosplenial cingulate gyrus, found to be metabolically affected in persons affected by or at risk for AD, and in brain regions known to participate with retrosplenial cingulate in networks contributing to spatial learning deficits found in these animals. Like patients with AD, PSAPP mice have age-related metabolic reductions in posterior cingulate cortex, a finding that does not appear to be related to morphological abnormalities. If longitudinal studies support these progressive and preferential reductions in retrosplenial metabolism in PSAPP mice, these reductions could provide an indicator of disease progression, help bridge the gap between human and animal studies of AD, and aid in clarification of disease mechanisms and screening of promising treatments.

Aging↗
PubMed2006

Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice.

Intraneuronal alpha-synuclein (alphaSYN) inclusions constitute the hallmark lesions of a number of neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies. In a transgenic mouse model expressing mutant [A30P]alphaSYN under control of the pan-neuronal Thy1 promoter, motor impairment became significant beyond 17 months of age. Cognitive performance was measured in the Morris water maze and upon fear conditioning. At 4 months of age, transgenic mice performed like controls. However, performance in these tasks was significantly impaired in (Thy1)-h[A30P]alphaSYN mice at 12 months of age. After completion of the cognition tests, mice were sacrificed and the regional distribution of neuropathology was examined. In contrast to 4 months old animals, 12 months old transgenic mice showed alpha-synucleinopathy in several brain regions, including the central nucleus of the amygdala, which is involved in cognitive behavior of mice, and is susceptible to alphaSYN pathology in human patients. Thus, age-dependent fibrillization of alphaSYN in specific cortical regions concomitant with cognitive decline may reflect dementia with Lewy bodies in a transgenic mouse model.

Age Factors↗
PubMed2005

Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy.

OBJECTIVE: We studied a transgenic mouse model of human desmin-related cardiomyopathy with cardiac-specific expression of a 7-amino acid deletion mutation in desmin (D7-des) to test the hypothesis that impaired linkage between desmin and desmosomes alters expression and function of the electrical coupling protein, connexin43 (Cx43). METHODS: Expression of Cx43 and selected mechanical junctions proteins was characterized in left ventrices of D7-des and control mice by quantitative confocal microscopy and immunoblotting. Remodeling of gap junctions was also analyzed by electron microscopic morphometry. The electrophysiological phentoype of D7-des mice was characterized by electrocardiography and optical mapping of transmembrane voltage. RESULTS: Cx43 signal at intercalated disks was decreased by approximately 3-fold in D7-des ventricular tissue due to reductions in both gap junction number and size. Immunoreactive signal at cell-cell junctions was also reduced significantly for adhesion molecules and linker proteins of desmosomes and fascia adherens junctions. Electron microscopy showed decreased gap junction remodeling. However, immunoblotting showed that the total tissue content of Cx43 and mechanical junction proteins was not reduced, suggesting that diminished signal at cell-cell junctions was not due to insufficient protein expression, but to failure of these proteins to assemble properly within electrical and mechanical junctions. Remodeling of gap junctions in D7-des mice led to slowing of ventricular conduction as demonstrated by optical electrophysiological mapping. CONCLUSIONS: These results illustrate how a defect in a protein conventionally thought to fulfill a mechanical function in the heart can also lead to electrophysiological alterations that may contribute to arrhythmogenesis.

Animals↗
PubMed2005

Mitogenic effects of the up-regulation of minichromosome maintenance proteins in anaplastic thyroid carcinoma.

CONTEXT: Anaplastic thyroid carcinomas (ATC) are among the most aggressive human malignancies and are characterized by high mitotic activity. Minichromosome maintenance proteins (MCM) 2-7 are required to initiate eukaryotic DNA replication, and their overexpression has been associated with dysplasia and malignancy. OBJECTIVE: In an attempt to cast light on the mechanisms governing ATC, we evaluated MCM5 and MCM7 expression in human normal, papillary (PTC), and anaplastic thyroid samples, as well as in primary culture cells and transgenic mouse models. RESULTS: MCM5 and MCM7 expression was high in 65% of ATC and negligible in normal thyroid tissue and papillary thyroid carcinomas. In ATC, high MCM5 and MCM7 expression was paralleled by high levels of MCM2 and MCM6. An analysis of human ATC primary cell cultures and of a transgenic mouse model of ATC confirmed these findings. An increased transcription rate accounted for MCM7 up-regulation, because the activity of the MCM7 promoter was more than 10-fold higher in ATC cells compared with normal thyroid cells. Adoptive overexpression of wild-type p53, but not of its inactive (R248W and R273H) mutants, strongly down-regulated transcription from the MCM7 promoter, suggesting that p53 knock-out contributes to MCM7 up-regulation in ATC. Treatment with small inhibitory duplex RNAs, which decrease MCM7 protein levels, reduced the rate of DNA synthesis in ATC cells. CONCLUSION: MCM proteins are overexpressed in ATC and sustain the high proliferative capacity of ATC cells.

Animals↗
PubMed2005

Characterization of prostatic neuroendocrine cell line established from neuroendocrine carcinoma of transgenic mouse allograft model.

BACKGROUND: The role of neuroendocrine (NE) cells in prostate cancer remains unclear. A useful model is necessary to study the biology of NE cells. We herein describe the establishment and characterization of an immortalized cell line from an NE-10 allograft of murine prostatic NE carcinoma. METHODS: A novel cell line, designated NE-CS, was developed from an NE-10 allograft that was established from the ventral prostate of the LPB-T-antigen (Tag) transgenic mouse, line 10 (12T-10). We investigated the growth, karyotype, electron microscopic findings, expression of Tag and androgen receptor (AR), and tumorigenesis of the cells in athymic mice. RESULTS: The immortal cell line NE-CS was maintained in vitro for more than 2 years. The NE-CS cells had dendritic-like extensions with dense core granules in the cytoplasm and produced serotonin and somatostatin in conditioned medium. The cells expressed neither Tag nor AR. They showed androgen-independent growth in vitro and a hypotetraploid karyotype similar to the original NE-10 allograft. The NE-CS cells, which were subcutaneously inoculated into athymic mice, formed tumors with the NE phenotype. The tumors exhibited accelerated growth compared to the original NE-10 allograft. CONCLUSIONS: The established cell line has characteristics of NE differentiation and tumorigenic ability. This cell line may be a promising model to understand the molecular mechanisms associated with the acquisition of hormone refractory prostate cancer.

Animals↗
PubMed2002

CD40-CD40L interaction in Alzheimer's disease.

Increasing evidence supports a role of the CD40 receptor-CD40 ligand (CD40-CD40L) interaction in the pathogenesis of Alzheimer's disease (AD). It has previously been shown that this dyad acts synergistically with the Alzheimer amyloid-beta peptide to promote microglial activation. Reactive microglia produce potentially neurotoxic substances such as tumor necrosis factor alpha and the reactive oxygen species nitric oxide, which can induce bystander neuronal injury at high levels. When a transgenic mouse model of AD is crossed with an animal deficient in CD40L, the resulting phenotype is deficient in the gliosis observed in a mouse model of AD in which CD40L is present. Additionally, these crossed animals have complete absence of AD-like neuronal Tau hyperphosphorylation, a marker of the preneuronal tangle pathology in AD patients. This suggests that the CD40-CD40L system is a critical enhancer of microglial activation in an AD transgenic mouse model and that such activation is associated with an increase in a key indicator of neuronal stress. Conversely, the finding that reduced CD40-CD40L interaction is associated with reduced chronic microgliosis and Tau hyperphosphorylation supports the view that, in general, mechanisms that reduce microgliosis will be beneficial in AD.

Alzheimer Disease↗
PubMed1999

Nonrandom cytogenetic alterations in hepatocellular carcinoma from transgenic mice overexpressing c-Myc and transforming growth factor-alpha in the liver.

Identification of specific and primary chromosomal alterations during the course of neoplastic development is an essential part of defining the genetic basis of cancer. We have developed a transgenic mouse model for liver neoplasia in which chromosomal lesions associated with both the initial stages of the neoplastic process and the acquisition of malignancy can be analyzed. Here we analyze chromosomal alterations in 11 hepatocellular carcinomas from the c-myc/TGF-alpha double-transgenic mice by fluorescent in situ hybridization with whole chromosome probes, single-copy genes, and 4'-6-diamidino-2-phenylindole (DAPI-) and G-banded chromosomes and report nonrandom cytogenetic alterations associated with the tumor development. All tumors were aneuploid and exhibited nonrandom structural and numerical alterations. A balanced translocation t(5:6)(G1;F2) was identified by two-color fluorescent in situ hybridization in all tumors, and, using a genomic probe, the c-myc transgene was localized near the breakpoint on derivative chromosome der 6. Partial or complete loss of chromosome 4 was observed in all tumors with nonrandom breakage in band C2. Deletions of chromosome 1 were observed in 80% of the tumors, with the most frequent deletion at the border of bands C4 and C5. An entire copy of chromosome 7 was lost in 80% of the tumors cells. Eighty-five percent of the tumor cells had lost one copy of chromosome 12, and the most common breakpoint on chromosome 12 occurred at band D3 (28%). A copy of chromosome 14 was lost in 72%, and band 14E1 was deleted in 32% of the tumor cells. The X chromosome was lost in the majority of the tumor cells. The most frequent deletion on the X chromosome involved band F1. We have previously shown that breakages of chromosomes 1, 6, 7, and 12 were observed before the appearance of morphologically distinct neoplastic liver lesions in this transgenic mouse model. Thus breakpoints on chromosome 4, 9, 14, and X appear to be later events in this model of liver neoplasia. This is the first study to demonstrate that specific sites of chromosomal breakage observed during a period of chromosomal instability in early stages of carcinogenesis are later involved in stable rearrangements in solid tumors. The identification of the 5;6 translocation in all of the tumors has a special significance, being the first balanced translocation reported in human and mouse hepatocellular carcinoma and having the breakpoint near a tumor susceptibility gene and myc transgene site of integration. Moreover, its early occurrence indicates that this is a primary and relevant alteration to the initiation of the neoplastic process. In addition, the concordance between the breakpoints observed during the early dysplastic stage of hepatocarcinogenesis and the stable deletions of chromosomes 1, 4, 6, 7, 9, and 12 in the tumors provides evidence for preferential site of genetic changes in hepatocarcinogenesis.

Age Factors↗
PubMed2004

Altered circadian locomotor activity in APP23 mice: a model for BPSD disturbances.

Over the past decade, clinical Alzheimer's disease research has been challenged with an increased interest in noncognitive symptomatology, commonly referred to as behavioural and psychological signs and symptoms of dementia (BPSD). In accordance, major attention is being paid to behavioural alterations in the phenotyping of transgenic mouse models. Besides an age-dependent decline of cognitive functions, the APP23 model was previously shown to exhibit cage activity disturbances, reminiscent of diurnal rhythm disturbances in Alzheimer patients. To further scrutinize these observations, circadian patterns of horizontal locomotor activity were assessed in 3-, 6- and 12-month-old APP23 mice and wild-type littermates in a test paradigm continuously recording cage activity over a period ranging from 1 to 3 days. At the age of 3 months, APP23 profiles resembled the wild-type pattern to a large extent, although minor differences were already noticeable. Six-month-old APP23 mice displayed an altered activity profile with a first indication of increased activity during the second half of the active phase, reminiscent of sundowning behaviour in Alzheimer patients. This bimodal overnight activity pattern became even more evident at the age of 12 months. The APP23 model was therefore shown to display an age-dependent development of cage activity disturbances and sundowning-like behaviour. A comparison is made with actigraphic recordings of human Alzheimer patients exhibiting sundowning behaviour. This first report of diurnal rhythm disturbances and sundowning-like phenomena in a transgenic mouse model greatly adds to the validity of the APP23 model.

Age Factors↗