Ras-GRF2 regulates nestin-positive stem cell density and onset of differentiation during adult neurogenesis in the mouse dentate gyrus |
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| Affiliation: | 1. Institute of Anatomy, University of Leipzig, Liebigstr. 13, 04103 Leipzig, Germany;2. Cologne University Hospital, Department of Orthopedic and Trauma Surgery, Uniklinik Köln, 50924 Köln, Germany;3. Institute of Anatomy 1, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Köln, Germany;4. Department of Medical Cell Technology, Fraunhofer Research Institution for Marine Biotechnology and Institute of Medical and Marine Biotechnology, University of Lübeck, Mönkhofer Weg 239a, 23562 Lübeck, Germany;5. Institute of Pathology, Building 706, Langenbeckstr. 1, 55131 Mainz, Germany;6. Institute for Multiple Sclerosis Research, Department of Neuroimmunology, University Medical Centre Göttingen, Waldweg 33, 37073 Göttingen, Germany;7. Department of Neuroscience, University of Florida, 1149 Newell Dr, Gainesville, FL 32610, USA;1. Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de Chile, Independencia, 8380492, Chile;2. Department of Kinesiology, Faculty of Health Sciences, Universidad Católica del Maule, Talca, Chile;1. Departments of Pediatrics and Psychiatry, Emory School of Medicine, United States;2. Molecular and Systems Pharmacology, Emory University, United States;3. Yerkes National Primate Research Center, Emory University, United States;4. Department of Molecular Biophysics and Biochemistry, Yale University, United States;5. Interdepartmental Neuroscience Program, Yale University, United States;6. Department of Neuroscience, Yale School of Medicine, United States;1. Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA;2. Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA |
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| Abstract: | Various parameters of neurogenesis were analyzed in parallel in the two neurogenic areas (the Dentate Gyrus[DG] and the Subventricular Zone[SVZ]/Rostral Migratory Stream[RMS]/Main Olfactory Bulb[MOB] neurogenic system) of adult WT and KO mouse strains for the Ras-GRF1/2 genes (Ras-GRF1-KO, Ras-GRF2-KO, Ras-GRF1/2-DKO). Significantly reduced numbers of doublecortin[DCX]-positive cells were specifically observed in the DG, but not the SVZ/RMS/MOB neurogenic region, of Ras-GRF2-KO and Ras-GRF1/2-DKO mice indicating that this novel Ras-GRF2-dependent phenotype is spatially restricted to a specific neurogenic area. Consistent with a role of CREB as mediator of Ras-GRF2 function in neurogenesis, the density of p-CREB-positive cells was also specifically reduced in all neurogenic regions of Ras-GRF2-KO and DKO mice. Similar levels of early neurogenic proliferation markers (Ki67, BrdU) were observed in all different Ras-GRF genotypes analyzed but significantly elevated levels of nestin-immunolabel, particularly of undifferentiated, highly ramified, A-type nestin-positive neurons were specifically detected in the DG but not the SVZ/RMS/MOB of Ras-GRF2-KO and DKO mice. Together with assays of other neurogenic markers (GFAP, Sox2, Tuj1, NeuN), these observations suggest that the deficit of DCX/p-CREB-positive cells in the DG of Ras-GRF2-depleted mice does not involve impaired neuronal proliferation but rather delayed transition from the stem cell stage to the differentiation stages of the neurogenic process. This model is also supported by functional analyses of DG-derived neurosphere cultures and transcriptional characterization of the neurogenic areas of mice of all relevant Ras-GRF genotypes suggesting that the neurogenic role of Ras-GRF2 is exerted in a cell-autonomous manner through a specific transcriptional program. |
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