Versatile use of rtTA-expressing retroviruses in the study of neurodegeneration
نویسندگان
چکیده
The tetracycline-regulated transactivator (tTA) was used in combination with the E.coli tet operon (TetR) to induce the expression of target genes both in vivo and in vitro [1]. In this system, the activation of TetR occurs only after the binding of the tTA element. Thus, target genes will be overexpressed only in those cells in which TetR and tTA are co-expressed. Tissue or cell specificity depends on the promoter that drives the expression of tTA. In addition, the temporal control of gene expression is regulated by the presence of Tetracycline (or, more commonly, its analogue, Doxycycline, which crosses the blood-brain barrier easily). This molecule triggers a conformational change in tTA (natively active) that prevents its binding to TetR and suppresses transcription (tet-OFF system). More recently, variations in this system include the use of the reverse tetracycline-regulated transactivator (rtTA), which requires the presence of tetracycline to bind to tetR (tetON system). Numerous combinations of mice engineered by tTA/ TetR systems have been generated in recent decades. In this regard, a model of particular relevance in the study of Alzheimer disease (AD) is the GSK-3β overexpressing (GSK-3β-OE) mouse [2]. This line is obtained by crossing tetR-GSK-3β mice (which carry a bi-directional TetR promoter followed by a GSK-3β cDNA in one direction and a cDNA encoding β-Galactosidase (β-Gal) fused to a nuclear localization signal in the other) with CamKII/ tTA mice. Thus, in the resulting GSK-3β-OE mice, this kinase is overexpressed in hippocampal and cortical neurons [3]. These mice exhibit increased neuronal Tau phosphorylation. Although these animals mimic several features of the AD brain scenario, the overexpression
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