Transcriptional regulation of neural stem cell expansion in the adult hippocampus

eLife

William R Meara¹  Charlotte Herber¹  Debolina Ghosh¹  Alexia Zagouras¹  James Coleman¹  Yu-Tzu Shih²  Amar Sahay²  Nannan Guo²  Haley Zanga²  Ruslan Sadreyev³  Lai Ping Wong³  Kelsey D McDermott⁴  J Tiago Gonçalves⁴ 

[1] Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States;Harvard Stem Cell Institute, Cambridge, United States;Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States;Harvard Stem Cell Institute, Cambridge, United States;Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, United States;BROAD Institute of Harvard and MIT, Cambridge, United States;Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, United States;Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine; Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States;

关键词: neural stem cells;    symmetric self-renewal;    hippocampus;    adult hippocampal neurogenesis;    dentate gyrus;    Klf9;    Mouse;   

DOI  :  10.7554/eLife.72195

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY