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PubMed1995

Evaluation of tyrosinase minigene co-injection as a marker for genetic manipulations in transgenic mice.

The utility of tyrosinase minigene co-injection was evaluated as a visual marker for the generation and breeding of transgenic mice. In an evaluation of 39 transgenic founder animals and 44 transgenic lines five phenotypic patterns of pigmentation were consistently observed, including albino, dark, light, mottled and himalayan. In these studies co-injection of the tyrosinase minigene along with the transgene of interest (TOI) resulted in genomic integration of the two transgenes in 95% of the F0 generation. Co-segregation of transgenes occurred in 94% of doubly transgenic mice in the F1 generation, without dissociation in subsequent generations. All pigmented phenotypes proved useful for distinguishing homozygous from heterozygous F2 animals via backcross trials, while the light, mottled and himalayan phenotypes proved useful in visually discriminating between homozygous and heterozygous F2 animals. In addition, the light, mottled and himalayan phenotypes proved useful in determining segregation patterns of transgenes in the progeny of crosses between separate transgenic lines. Moreover, there appears to be a correlation between intensity of pigmentation and degree of expression of the co-injected TOI. These studies confirm that tyrosinase co-injection is a useful adjunct in transgenic mouse studies and can serve to reduce routine genetic validation of transgenic lines.

Animals↗
PubMed1997

Reduced fecundity in insulin-like growth factor-binding protein-1 transgenic mice.

Transgenic mice that overexpress insulin-like growth factor-binding protein-1 (IGFBP-1) demonstrate a reduced litter size compared to nontransgenic, wild-type mice derived from the same genetic background. To determine the mechanism underlying this phenomenon, we examined the number of ovulatory follicles per cycle in naturally mated transgenic and wild-type mice by counting the corpora lutea and the blastocysts harvested by uterine flushing. In addition, we investigated the effects of insulin-like growth factor-I (IGF-I) on blastocyst DNA synthesis and examined the effects of a transgenic maternal environment on fetal outcome by cross transfer of blastocysts. Significantly fewer corpora lutea were observed in ovaries from transgenic vs. wild-type mice (7.6 +/- 1.8 vs. 11.8 +/- 1.5), and fewer blastocysts were harvested from transgenic mice compared to wild-type mice (7.6 +/- 2.3 vs. 10.1 +/- 2.0). DNA content and basal DNA synthesis were similar in blastocysts from nontransgenic and transgenic mice. However, unlike wild-type blastocysts, transgenic blastocysts did not respond to IGF-I with an increase in DNA synthesis. To determine the effects of maternal environment on fetal outcome, a mixture of equal numbers of transgenic and nontransgenic blastocysts was transferred into foster mothers. The ratio of transgenic to nontransgenic pups was not significantly different from the theoretically predicted value of 1. However, the litter size was significantly reduced in wild-type compared to transgenic foster mothers. These data suggest that the reduced fecundity is due to reduced ovulation and blastocyst number. Furthermore, expression of the transgene in neither the blastocyst nor the maternal tissues had any significant negative effect on implantation or fetal wastage.

Animals↗
PubMed1997

A 5' differentially methylated sequence and the 3'-flanking region are necessary for H19 transgene imprinting.

The mouse H19 gene is expressed exclusively from the maternal allele. The imprinted expression of the endogenous gene can be recapitulated in mice by using a 14-kb transgene encompassing 4 kb of 5'-flanking sequence, 8 kb of 3'-flanking sequence, which includes the two endoderm-specific enhancers, and an internally deleted structural gene. We have generated multiple transgenic lines with this 14-kb transgene and found that high-copy-number transgenes most closely follow the imprinted expression of the endogenous gene. To determine which sequences are important for imprinted expression, deletions were introduced into the transgene. Deletion of the 5' region, where a differentially methylated sequence proposed to be important in determining parental-specific expression is located, resulted in transgenes that were expressed and hypomethylated, regardless of parental origin. A 6-kb transgene, which contains most of the differentially methylated sequence but lacks the 8-kb 3' region, was not expressed and also not methylated. These results indicate that expression of either the H19 transgene or a 3' DNA sequence is key to establishing the differential methylation pattern observed at the endogenous locus. Finally, methylation analysis of transgenic sperm DNA from the lines that are not imprinted reveals that the transgenes are not capable of establishing and maintaining the paternal methylation pattern observed for imprinted transgenes and the endogenous paternal allele. Thus, the imprinting of the H19 gene requires a complex set of elements including the region of differential methylation and the 3'-flanking sequence.

Animals↗
PubMed2001

Central 5-hydroxytryptamine-2A receptor expression in transgenic mice bearing a glucocorticoid receptor antisense.

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA that partially blocks glucocorticoid receptor expression were used to investigate the long-term effect of hypothalamic-pituitary-adrenal dysfunction on brain 5-hydroxytryptamine-2A (5-HT2A) receptor expression. The brain 5-HT2A receptor mRNA levels in transgenic mice were measured by in situ hybridization and compared to those in control mice. We also studied the effect of a 3-week treatment with fluoxetine on brain 5-HT2A receptor expression in the transgenic mice. No difference in 5-HT2A mRNA levels was observed between transgenic and control mice in cortical or striatal regions, and fluoxetine treatment was without effect. No difference in hypothalamic 5-HT2A mRNA levels was observed between transgenic and control mice, while fluoxetine treatment increased these levels in both transgenic as well as in the hypothalamic ventromedial and paraventricular nuclei of control mice. 5-HT2A receptor mRNA levels were similar in hippocampal CA1 and CA2 subregions of control and transgenic, but were lower in the CA3 and CA4 subregions of transgenic mice. Fluoxetine had no effect on 5-HT2A mRNA levels of transgenic mice but reduced control mouse 5-HT2A receptor mRNA levels in the CA3 subregion. These results suggest that impaired glucocorticoid receptor function can affect hippocampal 5-HT2A receptor expression in transgenic mice and that this is not corrected by fluoxetine treatment.

Animals↗
PubMed1997

Endocrine profile and neuroendocrine challenge tests in transgenic mice expressing antisense RNA against the glucocorticoid receptor.

A transgene expressing antisense RNA complementary to a fragment of the glucocorticoid receptor cDNA was incorporated into the mouse genome and resulted in a transgenic animal that has decreased glucocorticoid receptor function. The transgenic mice showed basal plasma ACTH and corticosterone levels similar to those of the normal control animals. We have further investigated changes in HPA axis regulation by use of different neuroendocrine challenge tests including a dexamethasone suppression test (DST). In comparison to normal mice, a tenfold higher dose of dexamethasone (i.e. 20 micrograms/100 g body weight) was required to suppress the basal corticosterone levels of transgenic mice. Dexamethasone (2 micrograms/100 g body weight) produced a long-lasting suppression of plasma ACTH and corticosterone levels in control mice, whereas in transgenic animals only a short-lasting decrease in ACTH levels was apparent. Corticotropin-releasing hormone (CRH) administration resulted in an enhanced response in plasma ACTH levels in transgenic mice, whereas the corticosterone response was markedly reduced. The discrepancy between ACTH and corresponding corticosterone secretions in transgenic mice could be attributed, in part, to a reduced sensitivity of the adrenal gland to stimulation by ACTH. Pituitaries of transgenic mice contained about 50% less proopiomelanocortin (POMC) mRNA than those of control animals. No significant differences were noted in the ACTH or protein contents of normal and transgenic mice pituitary glands although a slight increase in protein content of the transgenic mouse adrenal gland was apparent. In conclusion, transgenic mice with impaired GR function show major disturbances in HPA axis regulation which seem to be caused by the primary defect in conjunction with secondary modifications in, amongst others, pituitary CRH receptor system(s), sympathetic output and adrenal development. This mouse is therefore a useful model to study the consequences of life-long defective GR function and HPA axis regulation in general.

Adrenal Glands↗
PubMed1994

Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia.

BACKGROUND AND PURPOSE: We have demonstrated in a previous study that superoxide radicals play a role in the pathogenesis of cerebral infarction, using a transgenic mouse model of distal middle cerebral artery occlusion, permanent ipsilateral cerebral carotid artery occlusion, and 1-hour contralateral cerebral carotid artery occlusion that produced infarction only in the cortex. However, the role of superoxide radicals in reperfusion injury in transgenic mice overexpressing superoxide dismutase (SOD) is unknown. Using a mouse model of intraluminal blockade of middle cerebral artery that produced both cortical and striatal infarction, we now further examined the role of superoxide radicals in ischemic cerebral infarction after reperfusion in transgenic mice overexpressing human CuZn-SOD activity. METHODS: Transgenic mice of strain Tg HS/SF-218, carrying human SOD-1 genes, and nontransgenic littermates were anesthetized with chloral hydrate (350 mg/kg IP) and xylazine (4 mg/kg IP). Physiological parameters were maintained at a normal range using a 30% O2/70% N2O gas mixture inserted via an inhalation mask. Body temperature was maintained at 37 +/- 0.5 degrees C by using a heating pad throughout the studies. The middle cerebral artery occlusion was achieved with a 5-0 rounded nylon suture placed within the internal cerebral artery for 3 hours followed by the removal of the suture to allow reperfusion for another 3 hours. Cerebral infarct size in brain slices and infarct volume, neurological deficit, cortical blood flow, and glutathione levels were measured in both transgenic and nontransgenic mice. RESULTS: Compared with the nontransgenic mice, the infarcted areas were significantly decreased in coronal slices from transgenic mice. The infarct volume (in cubic millimeters) was reduced by 26% in transgenic mice after ischemia and reperfusion. This decrease in the infarct volume in transgenic mice closely paralleled the reduced neurological deficits. Introduction of the suture to block blood supply to the middle cerebral artery territory produced a rapid decrease in the relative surface blood flow in the ipsilateral core and the peri-ischemic (penumbra) areas. There were no significant differences in the local cerebral blood flow in the ischemic core or the penumbra areas between the transgenic and nontransgenic groups. However, the level of reduced glutathione in the penumbra area was significantly higher in transgenic mice than in nontransgenic mice, whereas there was no difference in the reduced glutathione levels in the ischemic core between these two groups. CONCLUSIONS: Our study demonstrated that superoxide radicals play a major role in the pathogenesis of cerebral infarction in reperfusion injury after a focal stroke. The reduction in infarct volume and neurological deficits is not dependent on the changes in cerebral blood flow but rather correlate with reduced oxidative stress in the ischemic brain tissue, which was indicated by the relatively high levels of endogenous reduced glutathione in transgenic mice.

Animals↗
PubMed1997

Osteochondrodysplasia occurring in transgenic mice expressing interferon-gamma.

In addition to various biological activities, interferon-gamma (IFN-gamma) inhibits bone resorption and collagen synthesis. We produced a transgenic mouse line expressing the murine IFN-gamma gene and protein in the bone marrow and thymus. Forty-five transgenic FVB/NCr mice, 23 days-9 months of age, were studied for anomalies in the skeletal system. The transgenic mice had short, wide, and deformed long bones. Young transgenic mice had epiphyseal plates severely thickened with zones of hypertrophy and degeneration with irregular metaphyseal borders. Cartilagenous masses were also observed in the metadiaphyseal marrow cavities. These lesions were primarily seen in long bones and ribs. Adult transgenic mice had residues of degenerated cartilagenous masses in the diaphyses. Many osteoclasts with well-developed ruffled borders were present on the metaphyseal cartilagenous masses in young transgenic mice. Adult transgenic mice had less prominent primary spongiosa with fewer osteoclasts at the metaphysis as compared with nontransgenic controls. The cortical bones of the transgenic mice were thinner and more immature compared with controls. Transgenic mice also had fractures, disruption of the epiphyseal plate, and degeneration of articular cartilage. Thus, the IFN-gamma transgenic mice developed a complex chondro-osseous lesion that was diagnosed as osteochondrodysplasia. The lesions may originate from primarily decreased matrix synthesis in bone and cartilage and also possible osteoclast-related changes caused by IFN-gamma overexpression in the bone marrow. Our IFN-gamma transgenic mouse will be a useful model to investigate the role of IFN-gamma in bone metabolism.

Acid Phosphatase↗
PubMed1992

Neuroendocrine function in adult female transgenic mice expressing the human growth hormone gene.

Adult female transgenic mice expressing the human GH (hGH) gene with mouse metallothionein-I promoter are sterile. To evaluate the hypothalamic-pituitary function in these animals, adult female transgenic mice and nontransgenic normal littermates were ovariectomized. On days 7 and 8 after ovariectomy, mice were injected with either oil or primed with 0.5 micrograms estradiol benzoate (EB) in oil, 24 h later treated with 10 micrograms EB/100 g body wt and a day later bled for measurements of FSH, LH, and PRL levels. Plasma gonadotropin and PRL levels were also measured in ovary-intact transgenic and normal siblings at estrus. Additional ovariectomized EB-treated transgenic mice and normal siblings were injected with either saline or GnRH in saline (1 ng/g body wt) and were bled 15 min later for determination of circulating hormone levels. At estrus, in transgenic mice, circulating FSH and PRL levels were significantly lower (FSH:P less than 0.001; PRL:P less than 0.025), but plasma LH concentrations were higher (P less than 0.001) than those in nontransgenic mice. As expected, ovariectomy significantly increased (P less than 0.001) circulating FSH and LH levels in both groups of mice relative to ovary-intact animals, but the increase in plasma LH levels was attenuated in transgenic mice. The suppressive effect of estrogen on circulating FSH and LH levels were similar in transgenic and nontransgenic mice. Treatment with GnRH significantly increased plasma FSH and LH levels in both transgenic and normal mice. However, the plasma FSH and LH responses to GnRH administration were significantly reduced (P less than 0.001) in transgenic mice. The results of these studies indicate that adult female transgenic mice expressing the hGH gene are hypoprolactinemic. Yet due to PRL-like activity of hGH, the gonadotropin secretion is altered. Thus, endogenously secreted hGH modulates the hypothalamic-pituitary function of adult female transgenic mice bearing the hGH gene.

Animals↗
PubMed1996

Targeted overexpression of Bcl-2 in ovaries of transgenic mice leads to decreased follicle apoptosis, enhanced folliculogenesis, and increased germ cell tumorigenesis.

We have generated transgenic mice overexpressing Bcl-2, an apoptosis suppression protein, in ovarian cells using the inhibit-alpha gene promoter/enhancer. Ovarian apoptotic DNA fragmentation induced in immature animals by a low dose (2 IU) of PMSG was suppressed by greater than 55% in transgenic mice compared to their wild-type littermates. Morphological and in situ DNA end-labeling analyses showed that granulosa cells in large antral follicles of wild-type animals undergo apoptosis, but most follicles in transgenic animals are healthy. When the animals were treated with a high dose (4 IU) of PMSG to stimulate follicular growth, spontaneous ovulation was observed in 14 of 23 (61%) of the transgenic animals, but in only 3 of 18 (17%) of wild-type siblings. Furthermore, transgenic females had a larger litter size (9.07 +/- 0.25 pups/litter; n = 29) than wild-type controls (7.54 +/- 0.26 pups/litter; n = 28; P < 0.01). These data suggested that decreased ovarian apoptosis in transgenic animals could lead to enhanced folliculogenesis and ovulatory potential. Moreover, aging transgenic mice are susceptible to the development of benign cystic ovarian teratoma (4 in 20 transgenic animals and 0 in 26 wild-type controls). Some tumor tissues showed respiratory and intestinal cell types, whereas others showed the development of central nervous system-like structures. Because the bcl-2 transgene in these animals is overexpressed in somatic cells, but not oocytes, these findings suggest that enhanced survival of selected somatic cells in transgenic mice could lead to germ cell tumorigenesis. Thus, overexpression of Bcl-2 protein in the ovary leads to decreased ovarian somatic cell apoptosis, enhanced folliculogenesis, and increased susceptibility to ovarian germ cell tumorigenesis in transgenic animals. The present mouse model allows future studies on intracellular signal pathways regulating follicular atresia and on the potential role of ovarian somatic cell factors in germ cell tumorigenesis.

Aging↗
PubMed2006

Changes in presenilin 2-binding Wnt proteins, behavior, amyloid-beta 42, gamma-secretase activity, and testosterone sensitivity in transgenic mice coexpressing tetracycline-controlled transactivator and human mutant presenilin 2.

Nonregulatable promoters have been mainly used to produce transgenic mice that express the human genes for Alzheimer's disease (AD). The aim of this study was to produce doubly transgenic mice expressing the regulatable tet promoter-controlled transactivator (tTA) and human mutant presenilin 2 (N141I, hPS2m) genes in order to examine the AD-related phenotypes at the basal and inducible levels. To achieve this, the first lineage of the transgenic line, expressing Tet/tTA and the second lineage of transgenic mice, expressing Tet/hPS2m, were created, and the doubly transgenic mice were produced by crossing the Tet/tTA-transgenic mice with the Tet/hPS2m-transgenic mice. The doubly transgenic mice and nontransgenic littermates were then treated with or without doxycycline. The results showed that removing doxycycline from the transgenic mice resulted in the induction of the transgene, a Wnt signaling defect, behavioral impairment, elevated amyloid-beta-42 and gamma-secretase activity compared with in the group given doxycyline. Moreover, the expression levels of the hPS2m transgene decreased gradually in the transgenic males, with clear changes becoming apparent between 2 and 4 wk of age. Castrating these males resulted in an increased expression level of the hPS2m gene. This was restored to the normal levels by treatment with testosterone. Therefore, tetregulated transgenic mice can be used to examine the effect of the basal or inducible expression levels of hPS2m on the pathology of AD at the "on/off" states at any stage of development.

Amyloid Precursor Protein Secretases↗
PubMed1997

Islet cell proliferation and apoptosis in insulin-like growth factor binding protein-1 in transgenic mice.

Transgenic mice which overexpress insulin-like growth factor binding protein-1 (IGFPB-1) demonstrate fasting hyperglycemia, hyperinsulinemia and glucose intolerance in adult life. Here we have examined the ontogeny of pancreatic endocrine dysfunction and investigated islet cell proliferation and apoptosis in this mouse model. In addition we have examined pancreatic insulin content in transgenic mice derived from blastocyst transfer into non-transgenic mice. Transgenic mice were normoglycemic at birth but had markedly elevated plasma insulin levels, 56.2 +/- 4.5 versus 25.4 +/- 1.5 pmol/l, p < 0.001, and pancreatic insulin concentration, 60.5 +/- 2.5 versus 49.0 +/- 2.6 ng/mg of tissue, P < 0.01, compared with wild-type mice. Transgenic mice derived from blastocyst transfer to wild-type foster mothers had an elevated pancreatic insulin content similar to that seen in pups from transgenic mice. There was an age-related decline in pancreatic insulin content and plasma insulin levels and an increase in fasting blood glucose concentrations, such that adult transgenic mice had significantly less pancreatic insulin than wild-type mice. Pancreatic islet number and the size of mature islets were increased in transgenic animals at birth compared with wild-type mice. Both islet cell proliferation, measured by 5-bromo-2'-deoxyuridine labeling, and apoptosis, assessed by the in situ terminal deoxynucleotidyl transferase and nick translation assay, were increased in islets of newborn transgenic mice compared with wild-type mice. In adult mice both islet cell proliferation and apoptosis were low and similar in transgenic and wild-type mice. Islets remained significantly larger and more numerous in adult transgenic mice despite a reduction in pancreatic insulin content. These data suggest that overexpression of IGFBP-1, either directly or indirectly via local or systemic mechanisms, has a positive trophic effect on islet development.

Animals↗
PubMed2004

Obesity and diabetes in transgenic mice expressing proSAAS.

ProSAAS is a neuroendocrine peptide precursor that potently inhibits prohormone convertase 1 in vitro. To explore the function of proSAAS and its derived peptides, transgenic mice were created which express proSAAS using the beta-actin promoter. The body weight of transgenic mice was normal until approximately 10-12 weeks, and then increased 30-50% over wild-type littermates. Adult transgenic mice had a fat mass approximately twice that of wild-type mice, and fasting blood glucose levels were slightly elevated. In the pituitary, the levels of several fully processed peptides in transgenic mice were not reduced compared with wild-type mice, indicating that the proSAAS transgene did not affect prohormone convertase 1 activity in this tissue. Because the inhibitory potency of proSAAS-derived peptides towards prohormone convertase 1 is much greater in the absence of carboxypeptidase E activity, the proSAAS transgene was also expressed in carboxypeptidase E-deficient Cpe (fat/fat) mice. Although the transgenic mice were born in the expected frequency, 21 of 22 proSAAS transgenic Cpe (fat/fat) mice died between 11 and 26 weeks of age, presumably due to greatly elevated blood glucose. The levels of several pituitary peptides were significantly reduced in the proSAAS transgenic Cpe (fat/fat) mice relative to non-transgenic Cpe (fat/fat) mice, suggesting that the transgene inhibited prohormone convertase 1 in these mice. Taken together, these results are consistent with a role for proSAAS-derived peptides as neuropeptides that influence body weight independently of their function as inhibitors of prohormone convertase 1.

Animals↗
PubMed2004

Overexpression of human IGF-II mRNA in the brain of transgenic mice modulates IGFBP-2 gene expression in the medulla oblongata.

The insulin-like growth factors, IGF-I and IGF-II, and their binding proteins play an important role in the growth and development of the central nervous system. In the brain, colocalization of IGFs and IGFBPs often occurs, suggesting that IGFBPs can modulate IGF action. In one strain of our human (h)IGF-II transgenic mice, which carry an hIGF-II transgene driven by the H-2Kb promoter, we found overexpression of hIGF-II in the brain, as measured by Northern blot analysis. To clarify the localization and influence of the hIGF-II transgene on different components of the GH-IGF axis in the brain, we studied the expression pattern of the hIGF-II transgene, endogenous IGF-I and IGF-II, and IGFBP-2, -3 and -5 in the brain of prepubertal 4-week-old mice, using nonradioactive in situ hybridization. We found that the hIGF-II transgene is exclusively expressed in neurons of the piriform cortex, the cerebral cortex, the medulla oblongata and the granular layer of the cerebellum. In general, this pattern is comparable to the expression pattern of endogenous IGF-I, with a few exceptions: there is no expression of IGF-I in the granular layer of the cerebellum, whereas the Purkinje cells of the cerebellum and thalamus both express IGF-I but no hIGF-II transgene. This hIGF-II transgene expression pattern contrasts markedly with endogenous IGF-II expression, which is mainly located in nonneuronal cells such as the meninges and choroid plexus, and in some nuclei of the medulla oblongata. The hIGF-II transgene affects neither endogenous IGF-I and IGF-II expression, nor the expression of IGFBP-3, which is located in the choroid plexus. Although the hIGF-II transgene is expressed in neuronal structures similar to IGF-I and IGFBP-5, it is not able to regulate IGFBP-5 expression, as has previously been reported for IGF-I. In the medulla oblongata, the IGFBP-2 expression level showed 10-fold upregulation by the transgene, suggesting a modulating role for IGFBP-2 at the hIGF-II transgene action in this region.

Animals↗
PubMed1999

Primary immune response in skin and skin-associated lymphoid tissue of interleukin-4 transgenic mice.

The interleukin-4 transgenic mice investigated here exhibit a ubiquitous expression of interleukin-4 in all organs, including the skin. In this study, the induction phase of oxazolone-induced local primary contact hypersensitivity and croton oil-induced irritant contact dermatitis in transgenic and wild-type mice was analysed. Compared to wild-type mice, the transgenic mice showed a decreased activation of the skin-draining lymph nodes but a strong hyperreactivity in the skin after topical sensitisation. In contrast to this, both the transgenic and the wild-type mice developed a strong and comparable inflammatory skin reaction after topical irritation. A striking increased expression level of tumour necrosis factor-alpha and macrophage inflammatory protein-2 genes were found in the skin of the transgenic mice during primary local contact hypersensitivity, while both the transgenic and the wild-type mice developed comparable expression levels of these cytokines during irritant contact dermatitis. Compared to wild-type mice, a strongly enhanced expression level of interleukin-6 transcripts derived from epidermal antigen presenting cells were detected in the skin of IL-4 transgenic mice, whereas in the skin-draining lymph nodes of transgenic mice significantly lower levels were detected. We conclude that the migration of epidermal antigen-presenting cells towards the skin-draining lymph nodes is reduced in transgenic mice, which could be due to the different cytokine balance in these mice strains. The atypical irritant-like reaction observed in transgenic mice after topical sensitisation is a phenomenon comparable to atopic diseases and therefore this transgenic strain might be a helpful model for investigating the immunopathophysiological features of these diseases.

Animals↗
PubMed2001

Influence of beta1 integrins on epidermal squamous cell carcinoma formation in a transgenic mouse model: alpha3beta1, but not alpha2beta1, suppresses malignant conversion.

Although aberrant integrin expression has been documented in many epithelial tumors, little is known about how integrins influence neoplastic progression. To examine this issue, transgenic mice in which the alpha2beta1 or alpha3beta1 integrin was expressed in the suprabasal epidermal layers via the involucrin promoter were subjected to skin carcinogenesis. Equal numbers of benign squamous papillomas were observed in transgenic and wild-type animals. However, the frequency of conversion of papillomas to malignant squamous cell carcinomas was much lower in alpha3beta1 transgenic than in alpha2beta1 transgenic and wild-type mice. No differences were observed in apoptosis or in the expression of endogenous integrins in transgenic and wild-type papillomas. However, alpha3beta1 transgenic papillomas displayed a diminished proliferative capacity and were more highly differentiated as judged by BrdUrd incorporation and keratin 10 expression, respectively, than alpha2beta1 transgenic and wild-type papillomas. Two proteins that associate with alpha3beta1 and not alpha2beta1 are extracellular matrix metalloproteinase inducer and CD81. Extracellular matrix metalloproteinase inducer expression correlated inversely with the degree of differentiation in normal epidermis and in transgenic and wild-type papillomas. Up-regulation of CD81 was observed in 100% of wild-type and 88% of alpha2beta1 transgenic papillomas but in only 25% of alpha3beta1 transgenic papillomas. CD81 was undetectable in untreated epidermis and strongly expressed in all transgenic and wild-type squamous cell carcinomas. Our results demonstrate that the alpha3beta1 integrin can suppress malignant conversion, and that the mechanism may involve CD81.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Alloreactive lymphocytes from T cell receptor (beta-chain) transgenic mice do not mediate a graft-versus-host reaction.

The injection of mature T cells into a tolerant or immunocompromised allogeneic host animal produces a graft versus host response (GVHR) that can result in splenomegaly, immunosuppression and death of the host animal. We demonstrate here that lymphocytes from T cell receptor beta-chain (TCR-beta) transgenic mice, in which the expression of the transgene inhibits endogenous beta- and gamma-gene rearrangements and thus causes abnormal T cell development, are unable to mediate a GVHR. The GVHR was measured after the injection of lymphocytes from transgenic mice into normal F1 mice and also after transplantation of bone marrow and lymphocytes from transgenic mice into lethally irradiated F1 recipients. In both systems, cells from transgenic mice failed to produce a significant GVHR. Cells from the transgenic mice were able to recognize the foreign histocompatibility Ag of the host in vitro and in vivo although the transgenic mice rejected skin grafts more slowly than controls. Thus, lymphocytes from transgenic mice were unable to produce a GVHR despite the presence of alloreactive T cells. These results suggest that lymphocytes from TCR-beta transgenic mice fail to mediate a GVHR either because lymphocytes with a single transgenic TCR-beta chain have a limited ability to recognize allogeneic cells in vivo or because the transgenic mice lack lymphocyte subsets that are important for the mediation of a GVHR.

Animals↗
PubMed1995

The Emu-bcl-2 transgene enhances antigen-induced germinal center formation in both BALB/c and SJL mice but causes age-dependent germinal center hyperplasia only in the lymphoma-prone SJL strain.

Emu-bcl-2 transgenic and littermate control BALB/c and SJL mice were immunized in the front footpads with trinitrophenylated Brucella abortus and the germinal center (GC) response in draining brachial lymph nodes was studied by staining with peanut agglutinin peroxidase and methyl green. Although the GCs induced were not larger in transgenic than in control young mice, there was a significant increase in the percentage of B cell follicles exhibiting GCs 7 to 8 days after primary and secondary antigen injections in the transgenic mice of both strains. In addition, glucocorticosteroid injected on day 7 after the primary injection caused a marked decrease in GCs in littermate controls but had no effect in the bcl-2 transgenic SJL mice. Antibody production to B. abortus was only slightly higher in transgenic than in control mice, but anti-TNP immunoglobulin M and G titers were significantly enhanced in the transgenic mice. The bcl-2 transgenic SJL mice, older than 6 months, showed the spontaneous appearance of large numbers of peanut agglutinin-binding GCs that greatly varied in size and were located without regard for the normal lymph node structure or follicle localization. This GC hyperplasia was seen in a large percent of the older transgenic SJL mice and never in similarly aged normal SJL or BALB/c mice with and without the bcl-2 transgene. Frank lymphomatous transformation of peanut agglutinin-binding germinal center-like areas was seen in lymph nodes and Peyer's patches of some of the older bcl-2 transgenic SJL mice. These results suggest that the tendency of SJL mice to develop GC-derived lymphomas synergizes with the presence of the bcl-2 transgene to cause the development of GC hyperplasia.

Aging↗
PubMed1993

Characterization of sarcoma cell lines from v-jun transgenic mice.

Wounding is a prerequisite for tumor formation in v-jun transgenic mice. The progression from wound to dermal sarcoma is a multistep process which, at some stage, results in an increase in transgene mRNA expression in tumor tissue. However, transgene expression in individual sarcoma cells stained for Jun protein cultures is heterogeneous. We cloned several cell lines from wound-related v-jun transgenic tumors to determine whether a relationship existed between the cellular growth properties and structure, expression, or function of the transgene. Cell lines with very high v-jun expression had a high cloning efficiency in soft agar and tumorigenicity in nude mice. However, for cell lines with an intermediate or low level of transgene expression there was no correlation between transgene expression and the transformed phenotype. There was also no correlation between transgene expression and individual cell line morphologies, growth rates, transgene genomic DNA copy number, or mRNA expression of jun-related genes. The tumor cell subclones (1-20.2, 3-24.3) with very low transgene expression, very poor cloning efficiency, and low tumorigenicity also showed reduced activator protein 1 DNA binding activity and had an increased expression of endogenous c-jun when compared to other tumor cell lines. Transfection of a v-jun expression vector into cell lines with poor cloning efficiency and low tumorigenicity enhanced both in vitro cloning and in vivo tumor formation. However, such overexpressed v-jun had no effect on NIH3T3 cells. Our studies show that expression of the v-jun transgene contributes to the transformed phenotype of tumor cell lines but that there are additional factors that determine growth properties in culture and in the animal.

Animals↗