Different posttranscriptional controls for the human neurofilament light and heavy genes in transgenic mice
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Neurofilament
The use of the Cre-loxP recombination system allows the conditional inactivation of genes in mice. The availability of transgenic mice in which the Cre recombinase expression is highly cell type specific is a prerequisite to successfully use this system. We previously have characterized regulatory regions of the mouse flk-1 gene sufficient for endothelial cell-specific expression of the LacZ reporter gene in transgenic mice. These regions were fused to the Cre recombinase gene, and transgenic mouse lines were generated. In the resulting flk-1-Cre transgenic mice, specificity of Cre activity was determined by cross-breeding with the reporter mouse lines Rosa26R or CAG-CAT-LacZ. We examined double-transgenic mice at different stages of embryonic development (E9.5-E16.5) and organs of adult animals by LacZ staining. Strong endothelium-specific staining of most vascular beds was observed in embryos older than E11.5 in one or E13.5 in a second line. In addition, the neovasculature of experimental BFS-1 tumors expressed the transgene. These lines will be valuable for the conditional inactivation of floxed target genes in endothelial cells of the embryonic vascular system.
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We generated mice that overexpress the sirtuin, SIRT1. Transgenic mice have been generated by knocking in SIRT1 cDNA into the beta-actin locus. Mice that are hemizygous for this transgene express normal levels of beta-actin and higher levels of SIRT1 protein in several tissues. Transgenic mice display some phenotypes similar to mice on a calorie-restricted diet: they are leaner than littermate controls; are more metabolically active; display reductions in blood cholesterol, adipokines, insulin and fasted glucose; and are more glucose tolerant. Furthermore, transgenic mice perform better on a rotarod challenge and also show a delay in reproduction. Our findings suggest that increased expression of SIRT1 in mice elicits beneficial phenotypes that may be relevant to human health and longevity.
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Transgenic mice are an important in vivo model for studying the function of single genes. Specific induction and tissue specific expression of the inserted genes are the great advantages of this system. However, there a risks in constructing transgenic mice and the interpretion of the experimental data. To prevent artefacts and to optimize the transgenic model, the experimental systems have to fulfill the following presets:
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Abstract: Ser 55 within the head domain of neurofilament light chain (NF‐L) is a target for phosphorylation by protein kinase A. To understand further the physiological role(s) of NF‐L Ser 55 phosphorylation, we generated transgenic mice with a mutant NF‐L transgene in which Ser 55 was mutated to Asp so as to mimic permanent phosphorylation. Two lines of NF‐L(Asp) mice were created and these animals express the transgene in many neurones of the central and peripheral nervous systems. Both transgenic lines display identical, early onset, and robust pathological changes in the brain. These involve the formation of NF‐L(Asp)‐containing perikaryal neurofilament inclusion bodies and the development of swollen Purkinje cell axons. Development of these pathologies was rapid and fully established in mice as young as 4 weeks of age. The two transgenic lines show no elevation of NF‐L, neurofilament middle chain (NF‐M), or neurofilament heavy chain (NF‐H), and transgenic NF‐L(Asp) represents only a minor proportion of total NF‐L protein. Because other published transgenic lines expressing higher levels of wild‐type NF‐L do not exhibit phenotypic changes that in any way resemble those in the NF‐L(Asp) mice and because the two different NF‐L(Asp) transgenic lines display identical neuropathological changes, it is likely that the pathological alterations observed in the NF‐L(Asp) mice are the result of properties of the mutant NF‐L. These results support the notion that phosphorylation of Ser 55 is a mechanism for regulating neurofilament organisation in vivo.
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What are transgenic mice and what do we learn from them? In this review, we focus on the generation of "classical" transgenic and "knock-out" mice. The establishment of transgenic and gene-targeted mice provides an unique tool to study the function(s) of a given gene in the context of a whole organism. Based on selected examples, we demonstrate the potential of this transgenic technology to understand the interactions between cells, organs and organ systems in genetically engineered mice.
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AIM:To analyze the tissue morphologic phenotype and liver gene expression profile of hB1F transgenic mice. METHODS:Transgene expression was analyzed with RT-PCR and Western blotting.For one of the transgenic mouse lines, tissue expression pattern of the transgene was also examined with immunochemical methods.Pathological analysis was used to examine the tissue morphologic phenotype of established transgenic mice.The liver gene expression profile of transgenic mice was analyzed with microchip, and some of the differentially expressed genes were verified with RT-PCR. RESULTS:The expressions of hB1F were shown in livers from 6 of 7 transgenic mouse lines.The overexpression of hB1F transgene did not cause pathological changes.Expressions of three genes were up-regulated, while down-regulation was observed for 25 genes. CONCLUSION:The overexpression of hB1F transgene may cause changes of gene expression profiles in the liver of transgenic mice.
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Transgenic mice have had a tremendous impact on biomedical research. Most researchers are familiar with transgenic mice that carry Cre recombinase (Cre) and how they are used to create conditional knockouts. However, some researchers are less familiar with many of the other types of transgenic mice and their applications. For example, transgenic mice can be used to study biochemical and molecular pathways in primary cultures and cell suspensions derived from transgenic mice, cell-cell interactions using multiple fluorescent proteins in the same mouse, and the cell cycle in real time and in the whole animal, and they can be used to perform deep tissue imaging in the whole animal, follow cell lineage during development and disease, and isolate large quantities of a pure cell type directly from organs. These novel transgenic mice and their applications provide the means for studying of molecular and biochemical events in the whole animal that was previously limited to cell cultures. In conclusion, transgenic mice are not just for generating knockouts.
Gene knockout
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