tetracycline and Brain-Injuries

Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) are widely expressed in the mature nervous system and are thought to mediate plasticity and repair. We report the generation of transgenic mice that can be induced to express a dominant-negative FGFR (dnFGFR) in select neuronal populations. We show that a modified Thy1 promoter [Vidal, M., Morris, R., Grosveld, F., and Spanopoulou, E. 1990. Tissue-specific control elements of the Thy-1 gene. EMBO J 9 833-840] can be used to drive widespread neuronal expression of the reverse tetracycline transactivator M2 (rtTA-M2 [Urlinger, S., Baron, U., Thellmann, M., Hasan, M.T., Bujard, H., and Hillen, W., 2000. Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc. Natl. Acad. Sci. U. S. A. 97, 7963-7968]), which after stimulation with doxycycline induces co-expression of dnFGFR in mosaic subpopulations of rtTA-M2-positive forebrain neurons, but not in hindbrain and spinal cord rtTA-M2-positive neurons. Expression of dnFGFR did not cause overt neurodegeneration, but led to increased neuronal vulnerability: four days after a stab injury, cell death was marked in the hippocampus of dnFGFR-expressing animals when compared to controls. The nuclear morphology of dying CA1 pyramidal cells suggested an apoptotic mechanism of cell death. These observations demonstrate the importance of endogenous FGFs in the maintenance of the nervous system.

Topics: Animals; Brain Injuries; Doxycycline; Fibroblast Growth Factors; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; Leukocyte Common Antigens; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Mutation; Neurites; Neurons; PC12 Cells; Promoter Regions, Genetic; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Receptor, Fibroblast Growth Factor, Type 1; Tetracycline; Thy-1 Antigens; Trans-Activators; Transgenes

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Brain Injuries; Bronchi; Cerebrovascular Disorders; Female; Humans; Male; Middle Aged; Postoperative Care; Tetanus; Tetracycline; Tracheotomy