Neuronal vulnerability in transgenic mice expressing an inducible dominant-negative FGF receptor.
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.
Department of Neurology and Department of Anatomy and Neurobiology, College of Medicine, University of Vermont, HSRF 408, VT 05405, USA. Felix.Eckenstein@uvm.edu
Felix P
FP
Eckenstein
Toby
T
McGovern
Drew
D
Kern
Jason
J
Deignan
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D011401:Promoter Regions, Genetic; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000502:physiology*; D013752:Tetracycline / Q000494:pharmacology; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000494:pharmacology; D019076:Transgenes / Q000235:genetics
D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D018800:Thy-1 Antigens; D015534:Trans-Activators; D049452:Green Fluorescent Proteins; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D013752:Tetracycline; D004318:Doxycycline