Ras-GRF2 regulates nestin-positive stem cell density and onset of differentiation during adult neurogenesis in the mouse dentate gyrus
| Autor: | Eugenio Santos, Alberto Fernández-Medarde, Carmela Gómez, Rósula García-Navas, David Jimeno, Nuria Calzada |
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| Přispěvatelé: | Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Junta de Castilla y León, Asociación Española Contra el Cáncer, European Commission |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Doublecortin Protein Rostral migratory stream Neurogenesis Subventricular zone Biology Adult neurogenesis Nestin Mice 03 medical and health sciences Cellular and Molecular Neuroscience Neural Stem Cells Neurosphere medicine Animals Dentate gyrus Molecular Biology Guanine Nucleotide-Releasing Factor 2 Ras signaling Mice Knockout ras-GRF1 Cell Differentiation Cell Biology Ras-GRF2 Cell biology Doublecortin Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure nervous system Neural stem cell Dentate Gyrus biology.protein NeuN RasGEF Neuroscience |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1044-7431 |
| DOI: | 10.1016/j.mcn.2017.09.006 |
| Popis: | 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. Work supported by grants FIS PI16/02137 from ISCIII (MINECO) and SA043U16 (UIC 076) from JCyL, Spain. CG supported by a postdoctoral grant from the AECC. Research co-financed by FEDER funds. |
| Databáze: | OpenAIRE |
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