Abstract
Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors (TFs) in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of TFs regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show in mice that the TF Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital two-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a molecular blueprint for RGL symmetric self-renewal that was characterized by upregulation of genetic programs underlying Notch and mitogen signaling, cell cycle, fatty acid oxidation, and lipogenesis. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.
Highlights
MCM2 expression captures activated cells that have exited quiescence. To refine this estimation that is based on a surrogate (LacZ) of Kruppel-like factor 9 (Klf9) expression within the radial glial neural stem cells (RGLs) compartment, we performed Fluorescence in situ hybridization (FISH) using a Klf9 specific riboprobe and immunohistochemistry for GFP and BrdU on adult hippocampal sections obtained from Klf9 +/+ or LacZ/LacZ; Nestin GFP transgenic mice perfused 2 hours following a BrdU pulse (One-way ANOVA, F=5.6, p=0.04)(Figures 1C-E)
Central to experience-dependent regulation of neurogenesis is the ability of RGLs to constantly balance demands for neurogenesis and astrogenesis or RGL expansion with self-preservation through regulation of quiescence
Since interpretation of the external world is dependent on integration and convergence of physiological extracellular signals upon transcription factors (TFs) in RGLs, enriching and adverse experiences are likely to modulate the balance between transcriptional programs that regulate RGL division modes supporting amplification or asymmetric self-renewal [22]
Summary
In the adult mammalian brain, radial glial neural stem cells (RGLs) in the dentate gyrus subregion of the hippocampus give rise to dentate granule cells and astrocytes [1,2,3,4,5,6,7,8,9], a process referred to as adult hippocampal neurogenesis [10,11,12,13,14,15,16,17,18]. Levels of adult hippocampal neurogenesis are highly sensitive to experience [21, 22] suggesting that neurogenesis may represent an adaptive mechanism by which hippocampal dependent memory functions are optimized in response to environmental demands. Whereas enriching experiences (eg: complex environments, exploration, socialization) bias RGLs towards asymmetric divisions to generate astrocytes and neurons [23, 25], unfavorable conditions promote RGL quiescence (eg: chronic stress, aging) or symmetric self-renewal to support neural stem cell expansion at the expense of neurogenesis (eg: social isolation, seizures, aging)
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