Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction

Belteki, Gusztav; Haigh, Jody J.; Kabacs, Nikolett; Haigh, Katharina; Sison, Karen; Costantini, Frank; Whitsett, J. A.; Quaggin, Susan E.; Nagy, András

doi:10.1093/nar/gni051

Cited by 336 publications

(227 citation statements)

References 41 publications

(39 reference statements)

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“…The number of capillaries correlated with the number of proliferating hepatocytes (PCNA positive nuclei) and the expression levels of hVEGF-A 165 (Figure 4D). Similar results have been seen in transgenic mice which express hVEGF-A 165 in the liver [18], [29]–[30].…”

Section: Resultssupporting

confidence: 84%

Short and Long-Term Effects of hVEGF-A165 in Cre-Activated Transgenic Mice

et al. 2006

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We have generated a transgenic mouse where hVEGF-A165 expression has been silenced with loxP-STOP fragment, and we used this model to study the effects of hVEGF-A165 over-expression in mice after systemic adenovirus mediated Cre-gene transfer. Unlike previous conventional transgenic models, this model leads to the expression of hVEGF-A165 in only a low number of cells in the target tissues in adult mice. Levels of hVEGF-A165 expression were moderate and morphological changes were found mainly in the liver, showing typical signs of active angiogenesis. Most mice were healthy without any major consequences up to 18 months after the activation of hVEGF-A165 expression. However, one mouse with a high plasma hVEGF-A165 level died spontaneously because of bleeding into abdominal cavity and having liver hemangioma, haemorrhagic paratubarian cystic lesions and spleen peliosis. Also, two mice developed malignant tumors (hepatocellular carcinoma and lung adenocarcinoma), which were not seen in control mice. We conclude that long-term uncontrolled hVEGF-A165 expression in only a limited number of target cells in adult mice can be associated with pathological changes, including possible formation of malignant tumors and uncontrolled bleeding in target tissues. These findings have implications for the design of long-term clinical trials using hVEGF-A165 gene and protein.

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Section: Resultssupporting

confidence: 84%

Short and Long-Term Effects of hVEGF-A165 in Cre-Activated Transgenic Mice

et al. 2006

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“…Uncontrolled transgenic expression of a given gene typically leads to embryonic lethality that precludes further studies in adults [32]. For instance, a Gpr124 conditional knockout in the endothelia of adult mice resulted in BBB leakage in mouse models of both ischemic injury and glioblastoma [33].…”

Section: Discussionmentioning

confidence: 99%

Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation

Gong

Chen

Hong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Endothelial cell dysfunction is the principal pathological process underlying atherosclerotic cardiovascular disease. G protein-coupled receptor 124 (GPR124), an orphan receptor in the adhesion GPCR subfamily, promotes angiogenesis in the brain. In the present study, we explored the role of endothelial GPR124 in the development and progression of atherosclerosis in adult mice. Methods: Using tetracycline-inducible transgenic systems, we generated mice expressing GPR124 specifically under control of the Tie-2 promoter. The animal model of atherosclerosis was constructed by intravenously injecting AAV-PCSK9^DY into tetracycline-regulated mice and feeding the mice a high-fat diet for 16 consecutive weeks. Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of GPR124 in the pathological process of atherosclerosis. Results: Higher TC (total cholesterol) and LDL-C (low density lipoprotein cholesterol) levels in serum and greater lipid deposition in the aortic sinus were found in atherosclerotic mice with GPR124 overexpression, coincident with the elevated proliferation of smooth muscle cells. We observed an elevation of ONOO^- in the aortic sinus in this model by using immunofluorescence, and the experiments showed that the specific overexpression of GPR124 in the endothelium induced the up-regulation of CD68, NLRP3 and caspase-1 levels in the aortic sinus. Conclusion: The above results indicate that manipulating GPR124 in the endothelium may contribute to delayed pathological progression of atherosclerosis.

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“…Eremina et al [8] have shown that unrestricted expression of VEGF 165 during development is significantly detrimental, which taken together with these results suggest a balance of pro-angiogenic/anti-angiogenic VEGF-A is required for normal development and function [8, 9, 31, 45, 46]. Expression of VEGF xxx b isoforms and crucially the control of distal and proximal 3′-end splicing control during kidney development may therefore play a significant role in the modulation of VEGF xxx -driven responses.…”

Section: Discussionmentioning

confidence: 99%

The Alternatively Spliced Anti-Angiogenic Family of VEGF Isoforms VEGF<sub>xxx</sub>b in Human Kidney Development

et al. 2008

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Background/Aim: Vascular endothelial growth factor (VEGF), required for renal development, is generated by alternative splicing of 8 exons to produce two families, pro-angiogenic VEGF_xxx, formed by proximal splicing in exon 8 (exon 8a), and anti-angiogenic VEGF_xxxb, generated by distal splicing in exon 8 (exon 8b). VEGF₁₆₅b, the first described exon 8b-containing isoform, antagonises VEGF₁₆₅ and is anti-angiogenic in vivo. Methods: Using VEGF_xxxb-specific antibodies, we investigated its expression quantitatively and qualitatively in developing kidney, and measured the effect of VEGF₁₆₅b on renal endothelial and epithelial cells. Results: VEGF_xxxb formed 45% of total VEGF protein in adult renal cortex, and VEGF₁₆₅b does not increase glomerular endothelial cell permeability, it inhibits migration, and is cytoprotective for podocytes. During renal development, VEGF_xxxb was expressed in the condensed vesicles of the metanephros, epithelial cells of the comma-shaped bodies, invading endothelial cells and epithelial cells of the S-shaped body, and in the immature podocytes. Expression reduced as the glomerulus matured. Conclusion: These results show that the anti-angiogenic VEGF_xxxb isoforms are highly expressed in adult and developing renal cortex, and suggest that the VEGF_xxxb family plays a role in glomerular maturation and podocyte protection by regulating the pro-angiogenic pro-permeability properties of VEGF_xxx isoforms.

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Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction

Cited by 336 publications

References 41 publications

Short and Long-Term Effects of hVEGF-A165 in Cre-Activated Transgenic Mice

Short and Long-Term Effects of hVEGF-A165 in Cre-Activated Transgenic Mice

Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation

The Alternatively Spliced Anti-Angiogenic Family of VEGF Isoforms VEGF<sub>xxx</sub>b in Human Kidney Development

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