| Popis: |
In the adult mammalian brain, the ventricular-subventricular zone (V-SVZ) generates neurons and glia throughout life. In this germinal niche, neural stem cells (NSCs) coexist in quiescent and activated states. However, the molecular mechanisms underlying this transition remain elusive. miRNAs have been implicated in stem cell self-renewal and differentiation, but their role in adult NSC activation is unknown. By performing miRNA profiling of FACS-purified quiescent and activated adult V-SVZ NSCs, we identified the miR-17~92 cluster as highly upregulated in activated stem cells in comparison to their quiescent counterparts. Conditional deletion of miR-17~92 in FACS-purified adult NSCs reduced NSC proliferation in vitro. In vivo, miR-17~92 deletion in NSCs decreased NSC activation, proliferation, and neurogenesis. Unexpectedly, it also led to increased oligodendrogenesis in the V-SVZ, corpus callosum and septum, due to an expansion of OLIG2+ transit-amplifying cells (TACs). Finally, bioinformatic analysis of predicted miR-17~92 targets upregulated in qNSCs versus aNSCs identified S1pr1 and Pdgfrb as promising potential miR-17~92 targets for stem cell activation. In addition, pathway analysis unveiled a gene category related to oligodendrogenesis among the gene categories enriched for miR-17~92 targets. We validated Pdgfrα, a key regulator of oligodendrocyte generation, as a miR-17~92 target by luciferase assay and in vivo analysis. Together, these data uncover multiple functions of the miR-17~92 cluster in adult NSC activation and proliferation, and in the regulation of the balance between neurogenesis and oligodendrogenesis from TACs. |
