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PubMed1998

Impaired ability of Cftr knockout mice to control lung infection with Pseudomonas aeruginosa.

The present study was aimed at investigating the innate susceptibility of C57BL/6-Cftrunc/Cftrunc knockout [B6-Cftr (-/-)] mice to pulmonary infection with Pseudomonas aeruginosa. Our results indicate that 58.4% of B6-Cftr (-/-) mice died within 6 d following lung infection with 10(5) P. aeruginosa entrapped in agar beads, whereas only 12.1% of B6-Cftr (+/+) mice died over the same period of time. Moreover, the number of bacteria recovered from the lungs of B6-Cftr (-/-) mice 3 and 6 d after infection was significantly higher than that observed in their littermate controls. No correlation was found between the weight or age of the animals and the number of viable bacteria recovered from the lungs of mice. Histopathological examination of lung sections from P. aeruginosa-infected mice revealed that the infection results in a severe bronchopneumonia. Both B6-Cftr (-/-) knockout mice and their littermate controls developed similar lung pathology during the course of infection. Overall, results reported in the present study suggest that a defect at the Cftr locus leads to an exacerbation of P. aeruginosa lung infection resulting in a dramatically increased mortality rate and higher bacterial load.

Animals↗

PubMed2003

Beta 2 microglobulin knockout mice are resistant to lethal intraabdominal sepsis.

beta 2 microglobulin knockout (beta2M-/-) mice lack CD8+ T and natural killer T cells. We hypothesized that beta 2M-/- mice are resistant to lethal intraabdominal sepsis. To test this hypothesis, mortality, cytokine production, and physiologic function were assessed in beta 2M-/- mice during sepsis caused by cecal ligation and puncture (CLP). beta 2M-/- mice survived significantly longer than wild-type mice after CLP but ultimately exhibited 100% mortality. Treatment of beta 2M-/- mice with anti-asialoGM1 to deplete natural killer cells conferred greater than 70% long-term survival. Compared with wild-type mice, beta 2M-/- mice treated with anti-asialoGM1 produced decreased amounts of proinflammatory cytokines and did not exhibit hypothermia or metabolic acidosis after CLP. Adoptive transfer of CD8+ T and natural killer cells into beta 2M-/- mice treated with anti-asialoGM1 re-established CLP-induced mortality. CD8 knockout mice treated with anti-asialoGM1, which are specifically deficient in CD8+ T and natural killer cells, exhibited 40% long-term survival after CLP. Furthermore, treatment of wild-type mice with antibodies to CD8 and asialoGM1 conferred a significant survival benefit compared with wild-type mice treated with nonspecific IgG. These findings demonstrate that beta 2M-/- mice treated with anti-asialoGM1 are resistant to CLP-induced mortality and that depletion of CD8+ T and natural killer cells largely accounts for the survival benefit observed in these mice.

Adoptive Transfer↗

PubMed2003

Transplantation of syngeneic Schwann cells to the retina of the rhodopsin knockout (rho(-/-)) mouse.

PURPOSE: To determine whether subretinal Schwann cell transplantation can prolong the survival of photoreceptors in the rhodopsin knockout (rho(-/-)) mouse. METHODS: Schwann cells were prepared from postnatal day (PN) 5 to 7 mouse pups and grafted subretinally into the eyes of PN35 rho(-/-) mice. RT-PCR was performed on similarly prepared cells to determine growth factor production in vitro. Eyes were retrieved at PN70 for anatomic and statistical analysis. Control animals received grafts of fibroblasts or sham surgery. RESULTS: RT-PCR demonstrated the presence of message for ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), and glia-derived neurotrophic factor (GDNF) in the cultured Schwann cells. Schwann cell grafts produced a statistically significant rescue of photoreceptors in a restricted area of retina at PN70, but the effect was lost by PN140. Preserved inner segments could be identified, but outer segments were never present. Sham surgery also resulted in photoreceptor rescue but at a reduced level. Fibroblast grafts appeared to produce little or no rescue effect. Grafts of Schwann cells or fibroblasts and sham surgery induced a reactive Müller glial response. CONCLUSIONS: Schwann cells can prolong photoreceptor survival in the rhodopsin knockout mouse until at least PN70.

Animals↗

PubMed2003

Genetic background influences cataractogenesis, but not lens growth deficiency, in Cx50-knockout mice.

PURPOSE: Deletion of connexin (Cx)50 produces microphthalmia with nuclear cataracts. To determine whether these two traits are influenced by genetic background and are dependent on each other, mice carrying the Cx50 deletion in two different strains were generated, and the growth defect and severity of cataracts were analyzed. METHODS: Cx50-knockout mice were generated in the 129S6 strain, and back-crossed into the C57BL/6J genetic background. To analyze the influence of genetic background on the observed phenotype, postnatal lens growth, lens clarity, lens histology and crystallin solubility were determined and compared between the two strains of Cx50-knockout mice. RESULTS: The growth deficiency persisted, regardless of genetic background, but genetic modifiers that differentially altered the solubility of crystallin proteins influenced the severity of cataracts. Expression levels of Cx46 were similar in all animals, regardless of genetic background, indicating that the differences were not due to a compensatory upregulation of Cx46. CONCLUSIONS: Taken together, these data indicate that the two components of the Cx50 phenotype are independent of each other and that cataractogenesis is under the influence of an unidentified genetic modifier.

Animals↗

PubMed1998

Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E.

Apo E is a key molecule in the lipoprotein metabolism; thus, genetic manipulation of apo E may prove useful in the treatment of hypercholesterolemia. To test the feasibility of this idea, we have generated low density lipoprotein receptor (LDLR) knockout mice that overexpress the rat apo E transgene (ETg+/+:LDLRKO), and compared their plasma lipoprotein profiles with those of nonexpressing LDLR knockout mice (ETg-/-:LDLRKO). On a normal chow diet, the mean plasma cholesterol level of ETg+/+:LDLRKO mice was significantly lower than that of ETg-/-:LDLRKO mice (189 versus 240 mg/dl, P < 0. 01). The LDL fraction was selectively reduced in the ETg+/+:LDLRKO mice. Despite the challenge with an atherogenic diet, cholesterol lowering was persistently observed and fatty streak lesions in the aortic sinus were significantly suppressed in the mice overexpressing apo E. These results imply that stimulation of hepatic production of apo E may be used as a promising adjunctive therapy for homozygous familial hypercholesterolemia.

Animals↗

PubMed1996

Profound induction of hepatic cholesteryl ester transfer protein transgene expression in apolipoprotein E and low density lipoprotein receptor gene knockout mice. A novel mechanism signals changes in plasma cholesterol levels.

The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to other lipoproteins and is a key regulated component of reverse cholesterol transport. Dietary hypercholesterolemia results in increased hepatic CETP gene transcription and higher plasma CETP levels. To investigate the mechanisms by which the liver senses hypercholesterolemia, mice containing a natural flanking region CETP transgene (NFR-CETP transgene) were bred with apo E or LDL receptor gene knockout mice (E0 or LDLr0 mice). Compared to NFR-CETP transgenic (Tg) mice with intact apo E genes, in NFR-CETP Tg/E0 mice there was an eightfold induction of plasma CETP levels and a parallel increase in hepatic CETP mRNA levels. Other sterol-responsive genes (LDL receptor and hydroxymethyl glutaryl CoA reductase) also showed evidence of altered regulation with decreased abundance of their mRNAs in the E0 background. A similar induction of plasma CETP and hepatic CETP mRNA levels resulted from breeding the NFR-CETP transgene into the LDL receptor gene knockout background. When placed on a high cholesterol diet, there was a further increase in CETP levels in both E0 and LDLr0 backgrounds. In CETP Tg, CETP Tg/E0, and CETP Tg/LDLr0 mice on different diets, plasma CETP and CETP mRNA levels were highly correlated with plasma cholesterol levels. The results indicate that hepatic CETP gene expression is driven by a mechanism which senses changes in plasma cholesterol levels independent of apo E and LDL receptors. Hepatic sterol-sensitive genes have mechanisms to sense hypercholesterolemia that do not require classical receptor-mediated lipoprotein uptake.

Animals↗

PubMed1996

Magnetic resonance evidence of hypoxia in a homozygous alpha-knockout of a transgenic mouse model for sickle cell disease.

All transgenic mouse models for sickle cell disease express residual levels of mouse globins which complicate the interpretation of experimental results. We now report on a mouse expressing high levels of human betaS and 100% human alpha-globin. These mice were created by breeding the alpha-knockout and the mouse beta(major)-deletion to homozygosity in mice expressing human alpha- and betaS-transgenes. These betaS-alpha-knockout mice have accelerated red cell destruction, altered hematological indices, ongoing organ damage, and pathology under ambient conditions which are comparable with those found in alphaH betaS-Ant[betaMDD] mice without introduction of additional mutations which convert betaS into a "super-betaS" such as the doubly mutated betaS-Antilles. This is of particular importance for testing strategies for gene therapy of sickle cell disease. Spin echo magnetic resonance imaging at room air and 100% oxygen demonstrated the presence of blood hypoxia (high levels of deoxygenated hemoglobin) in the liver and kidneys that was absent in control mice. We demonstrate here that transgenic mice can be useful to test new noninvasive diagnostic procedures, since the magnetic resonance imaging technique described here potentially can be applied to patients with sickle cell disease.

Anemia, Sickle Cell↗

PubMed1998

Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice.

Atherosclerosis is associated with immune activation. T cells and macrophages infiltrate atherosclerotic plaques and disease progression is associated with formation of autoantibodies to oxidized lipoproteins. In the apo E knockout mouse, a genetic model of cholesterol-induced atherosclerosis, congenital deficiency of macrophages, lymphocytes, or interferon-gamma receptors result in reduced lesion formation. We have now evaluated whether immune modulation in the adult animal affects disease development. Injections of 7-wk-old male apo E knockout mice with polyclonal immunoglobulin preparations (ivIg) during a 5-d period reduced fatty streak formation over a 2-mo period on cholesterol diet by 35%. Fibrofatty lesions induced by diet treatment for 4 mo were reduced by 50% in mice receiving ivIg after 2 mo on the diet. ivIg treatment also reduced IgM antibodies to oxidized LDL and led to inactivation of spleen and lymph node T cells. These data indicate that ivIg inhibits atherosclerosis, that it is effective both during the fatty streak and plaque phases, and that it may act by modulating T cell activity and/or antibody production. Therefore, immunomodulation may be an effective way to prevent and/or treat atherosclerosis.

Adjuvants, Immunologic↗

PubMed2001

Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance.

To investigate the physiological function of syntaxin 4 in the regulation of GLUT4 vesicle trafficking, we used homologous recombination to generate syntaxin 4-knockout mice. Homozygotic disruption of the syntaxin 4 gene results in early embryonic lethality, whereas heterozygous knockout mice, Syn4(+/-), had normal viability with no significant impairment in growth, development, or reproduction. However, the Syn4(+/-) mice manifested impaired glucose tolerance with a 50% reduction in whole-body glucose uptake. This defect was attributed to a 50% reduction in skeletal muscle glucose transport determined by 2-deoxyglucose uptake during hyperinsulinemic-euglycemic clamp procedures. In parallel, insulin-stimulated GLUT4 translocation in skeletal muscle was also significantly reduced in these mice. In contrast, Syn4(+/-) mice displayed normal insulin-stimulated glucose uptake and metabolism in adipose tissue and liver. Together, these data demonstrate that syntaxin 4 plays a critical physiological role in insulin-stimulated glucose uptake in skeletal muscle. Furthermore, reduction in syntaxin 4 protein levels in this tissue can account for the impairment in whole-body insulin-stimulated glucose metabolism in this animal model.

Adipocytes↗

PubMed2003

Stem cell factor restores hepatocyte proliferation in IL-6 knockout mice following 70% hepatectomy.

Stem cell factor (SCF) is a molecule with known proliferative effects on hematopoietic cells. More recent studies suggest that this molecule may also have effects on cellular differentiation and proliferation in other types of cells. The current investigations demonstrate that there is a large reservoir of SCF in the liver, that hepatic SCF levels change dramatically following partial hepatectomy in mice, and that SCF blockade, either by administration of anti-SCF antibodies or by using genetically altered, SCF-deficient mice, inhibits hepatocyte proliferation after partial hepatectomy; if SCF is replaced in the genetically SCF-deficient mice after partial hepatectomy, hepatocyte proliferation is restored to that seen in WT animals. Furthermore, SCF administration to IL-6 knockout mice also restores hepatocyte proliferation to normal. In vitro studies using primary mouse hepatocytes demonstrate that SCF causes hepatocyte proliferation and is induced by IL-6 and that treatment with anti-SCF antibodies inhibits IL-6-induced hepatocyte proliferation. Further in vivo studies in IL-6 knockout mice demonstrate that SCF administration to these animals increases p-stat3 levels, suggesting that the SCF-induced increase in hepatocyte proliferation in this system is stat3-mediated.

Animals↗

PubMed1999

Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.

A deficiency in microsomal triglyceride transfer protein (MTP) causes the human lipoprotein deficiency syndrome abetalipoproteinemia. However, the role of MTP in the assembly and secretion of VLDL in the liver is not precisely understood. It is not clear, for instance, whether MTP is required to move the bulk of triglycerides into the lumen of the endoplasmic reticulum (ER) during the assembly of VLDL particles. To define MTP's role in hepatic lipoprotein assembly, we recently knocked out the mouse MTP gene (Mttp). Unfortunately, achieving our objective was thwarted by a lethal embryonic phenotype. In this study, we produced mice harboring a "floxed" Mttp allele and then used Cre-mediated recombination to generate liver-specific Mttp knockout mice. Inactivating the Mttp gene in the liver caused a striking reduction in VLDL triglycerides and large reductions in both VLDL/LDL and HDL cholesterol levels. The Mttp inactivation lowered apo B-100 levels in the plasma by >95% but reduced plasma apo B-48 levels by only approximately 20%. Histologic studies in liver-specific knockout mice revealed moderate hepatic steatosis. Ultrastructural studies of wild-type mouse livers revealed numerous VLDL-sized lipid-staining particles within membrane-bound compartments of the secretory pathway (ER and Golgi apparatus) and few cytosolic lipid droplets. In contrast, VLDL-sized lipid-staining particles were not observed in MTP-deficient hepatocytes, either in the ER or in the Golgi apparatus, and there were numerous cytosolic fat droplets. We conclude that MTP is essential for transferring the bulk of triglycerides into the lumen of the ER for VLDL assembly and is required for the secretion of apo B-100 from the liver.

Alleles↗

PubMed1998

Increased sphingomyelin content of plasma lipoproteins in apolipoprotein E knockout mice reflects combined production and catabolic defects and enhances reactivity with mammalian sphingomyelinase.

Apolipoprotein E knockout (apoE0) mice accumulate atherogenic remnant lipoproteins in plasma. We now provide evidence that these particles are enriched in sphingomyelin (SM), and explore the mechanisms and possible pathophysiological consequences of this finding. The phosphatidylcholine/sphingomyelin (PC/SM) ratio was reduced in all lipoproteins in apoE0 mice compared with wild-type (Wt) mice (2.0+/-0.2 vs. 4.7+/-0.5; 2.8+/-0.5 vs. 5.5+/-0.9; 1.9+/-0. 5 vs. 4.6+/-0.5 for VLDL, LDL, and HDL), reflecting 400 and 179% increases in plasma pools of SM and PC, respectively. Turnover studies using [14C]PC/[3H]SM VLDL or HDL showed that the fractional catabolic rate (FCR) of VLDL-SM and HDL-SM were markedly reduced in the apoE0 mice compared with Wt mice, while the FCRs of VLDL-PC and HDL-PC were similar. By contrast, the FCRs of [3H]PC ether and [14C]SM were identical in apoE0 and Wt mice. The production rates of VLDL-SM and HDL-SM in apoE0 mice were much higher than in Wt mice, while the production rates of lipoprotein PC were similar. To assess the underlying mechanisms, we also measured the PC/SM ratio in VLDL and LDL of LDL receptor knockout (LDLr0) and hepatic LDL receptor-related protein knockout/LDLr0 mice, but found no difference with Wt mice. Using S-sphingomyelinase, an enzyme secreted by macrophages and endothelial cells, we found that VLDL and LDL from apoE0, but not from Wt or LDLr0 mice, were significantly aggregated, and that aggregation was not prevented by adding back apoE. We then enriched the apoE0-VLDL and Wt-VLDL with different amounts of SM, and found that VLDL aggregation was enhanced. Thus, the increased SM content of lipoproteins in apoE0 mice is due to combined synthesis and clearance defects. Impaired SM clearance reflects resistance to intravascular enzymes and delayed removal by a non-LDLr, non-LDLr related protein pathway. The increased SM content in slowly cleared remnant lipoproteins may enhance their susceptibility to arterial wall SMase and increase their atherogenic potential.

Acyltransferases↗

PubMed2000

Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus.

The development of experimental models of active autoimmune diseases can be difficult due to tolerance of autoantigens, but knockout mice, which fail to acquire tolerance to the defective gene product, provide a useful tool for this purpose. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we have generated an active disease model for this autoantibody-mediated disease. Dsg3(-/-) mice, but not Dsg3(+/-) littermates, produced anti-Dsg3 IgG that binds native Dsg3, when immunized with recombinant mouse Dsg3. Splenocytes from the immunized Dsg3(-/-) mice were then adoptively transferred into Rag-2(-/-) immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in the recipient mice for more than 6 months without further boosting. This IgG bound to Dsg3 in vivo and disrupted the cell-cell adhesion of keratinocytes. Consequently, the recipient mice developed erosions in their oral mucous membranes with typical histologic findings of PV. In addition, the recipient mice showed telogen hair loss, as found in Dsg3(-/-) mice. Collectively, the recipient mice developed the phenotype of PV due to the pathogenic anti-Dsg3 IgG. This model will be valuable for developing novel therapeutic strategies. Furthermore, our approach can be applied broadly for the development of various autoimmune disease models.

Animals↗

PubMed2003

Metabolic changes in the knockout mouse for Canavan's disease: implications for patients with Canavan's disease.

Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency, which leads to accumulation of N-acetylaspartic acid in the brain and blood and an elevated level of N-acetylaspartic acid in the urine. The brain of patients with Canavan's disease shows spongy degeneration. How the enzyme deficiency and elevated N-acetylaspartic acid cause the pathophysiology observed in Canavan's disease is not obvious. The creation of a knockout mouse for Canavan's disease is being used as a tool to investigate metabolic pathways in the mouse and correlate them with the patients with Canavan's disease. The level of glutamate is lower in the knockout mouse brain than in the wild-type mouse brain, similar to what we have found in children with Canavan's disease, and so are the levels of gamma-aminobutyric acid (GABA). The level of aspartate is higher in the Canavan's disease mouse brain. The activity of aspartate aminotransferase, an enzyme involved in the malate-aspartate shuttle, is lower in the Canavan's disease mouse brain. The lower weight of the Canavan's disease mouse was in direct proportion to low total-body fat and bone mineral density. These changes might be similar to what is seen in patients with Canavan's disease and could have therapeutic implications.

Animals↗

PubMed2001

Multipotent hematopoietic cell lines derived from C/EBPalpha(-/-) knockout mice display granulocyte macrophage-colony-stimulating factor, granulocyte- colony-stimulating factor, and retinoic acid-induced granulocytic differentiation.

The transcription factor C/EBPalpha is an important mediator of granulocyte differentiation and regulates the expression of multiple granulocyte-specific genes including the granulocyte-colony-stimulating factor (G-CSF) receptor, neutrophil elastase, and myeloperoxidase. Indeed C/EBPalpha knockout mice display a profound block in granulocyte differentiation. To study this block in granulocytic differentiation in more detail, retroviral vector-mediated transduction of a dominant-negative retinoic acid receptor was used to establish hematopoietic growth factor-dependent, lympho-myeloid progenitor cell lines from the fetal livers of both the C/EBPalpha knockout animals (C/EBPalpha(-/-)) and their heterozygous littermates (C/EBPalpha(+/-)). Surprisingly, the C/EBPalpha(-/-) cell lines displayed significant spontaneous granulocytic differentiation, and this differentiation was markedly enhanced when the cells were stimulated with granulocyte macrophage (GM)-CSF. This GM-CSF-mediated differentiation was associated with the up-regulation of G-CSF receptor mRNA, and the combination of GM-CSF and G-CSF generated more than 95% mature neutrophils in the C/EBPalpha(-/-) cultures. The addition of all-trans retinoic acid also enhanced this granulocytic differentiation of the cultured C/EBPalpha(-/-) cells, indicating that the activated retinoic acid receptors can enhance granulocytic differentiation through a molecular pathway that is independent of C/EBPalpha. These studies clearly indicate that terminal granulocytic differentiation associated with the up-regulation of C/EBPalpha-responsive genes can occur in the absence of C/EBPalpha, and they indicate the existence of multiple independent molecular pathways potentially used by primitive hematopoietic precursors that can lead to the development of mature granulocytes.

Animals↗

PubMed2004

The "Goldilocks effect" in cystic fibrosis: identification of a lung phenotype in the cftr knockout and heterozygous mouse.

BACKGROUND: Cystic Fibrosis is a pleiotropic disease in humans with primary morbidity and mortality associated with a lung disease phenotype. However, knockout in the mouse of cftr, the gene whose mutant alleles are responsible for cystic fibrosis, has previously failed to produce a readily, quantifiable lung phenotype. RESULTS: Using measurements of pulmonary mechanics, a definitive lung phenotype was demonstrated in the cftr-/- mouse. Lungs showed decreased compliance and increased airway resistance in young animals as compared to cftr+/+ littermates. These changes were noted in animals less than 60 days old, prior to any long term inflammatory effects that might occur, and are consistent with structural differences in the cftr-/- lungs. Surprisingly, the cftr+/- animals exhibited a lung phenotype distinct from either the homozygous normal or knockout genotypes. The heterozygous mice showed increased lung compliance and decreased airway resistance when compared to either homozygous phenotype, suggesting a heterozygous advantage that might explain the high frequency of this mutation in certain populations. CONCLUSIONS: In the mouse the gene dosage of cftr results in distinct differences in pulmonary mechanics of the adult. Distinct phenotypes were demonstrated in each genotype, cftr-/-, cftr +/-, and cftr+/+. These results are consistent with a developmental role for CFTR in the lung.

Animals↗

PubMed2006

Outcome of urogenital infection with Chlamydia muridarum in CD14 gene knockout mice.

BACKGROUND: CD14 has been postulated to play a role in chlamydial immunity and immunopathology. There is evidence to support this role in human infections but its function in a mouse model has not been investigated. METHODS: Female CD14 gene knockout and C57BL/6J wild type mice were infected intravaginally with Chlamydia muridarum. The infection course was monitored by detection of viable chlamydiae from serially collected cervical-vaginal swabs. The sequela of tubal factor infertility was assessed using hydrosalpinx formation as a surrogate marker. RESULTS: A significantly abbreviated infection course was observed in the CD14 gene knockout mice but hydrosalpinx formation occurred at similar rates between the two groups. CONCLUSION: Involvement of CD14 during chlamydial infection impedes infection resolution but this does not affect the sequela of infertility as assessed by hydrosalpinx formation.

Animals↗

PubMed2004

Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice.

INTRODUCTION: Ataxia-telangiectasia is an autosomal-recessive disease that affects neuro-immunological functions, associated with increased susceptibility to malignancy, chromosomal instability and hypersensitivity to ionizing radiation. Although ataxia-telangiectasia mutated (ATM) heterozygous deficiency has been proposed to increase susceptibility to breast cancer, some studies have not found excess risk. In experimental animals, increased susceptibility to breast cancer is not observed in the Atm heterozygous deficient mice (Atm+/-) carrying a knockout null allele. In order to determine the effect of Atm heterozygous deficiency on mammary tumourigenesis, we generated a series of Atm+/- mice on the p53+/- background with a certain predisposition to spontaneous development of mammary carcinomas, and we examined the development of the tumours after X-irradiation. METHODS: BALB/cHeA-p53+/- mice were crossed with MSM/Ms-Atm+/- mice, and females of the F1 progeny ([BALB/cHeA x MSM/Ms]F1) with four genotypes were used in the experiments. The mice were exposed to X-rays (5 Gy; 0.5 Gy/min) at age 5 weeks. RESULTS: We tested the effect of haploinsufficiency of the Atm gene on mammary tumourigenesis after X-irradiation in the p53+/- mice of the BALB/cHeA x MSM/Ms background. The singly heterozygous p53+/- mice subjected to X-irradiation developed mammary carcinomas at around 25 weeks of age, and the final incidence of mammary carcinomas at 39 weeks was 31% (19 out of 61). The introduction of the heterozygous Atm knockout alleles into the background of the p53+/- genotype significantly increased the incidence of mammary carcinoma to 58% (32 out of 55) and increased the average number of mammary carcinomas per mouse. However, introduction of Atm alleles did not change the latency of development of mammary carcinoma. CONCLUSION: Our results indicate a strong enhancement in mammary carcinogenesis by Atm heterozygous deficiency in p53+/- mice. Thus, doubly heterozygous mice represent a useful model system with which to analyze the interaction of heterozygous genotypes for p53, Atm and other genes, and their effects on mammary carcinogenesis.

Animals↗