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Cell Stem Cell. 2018 Sep 6;23(3):444-452.e4. doi: 10.1016/j.stem.2018.08.005. Epub 2018 Aug 30.

Autocrine Mfge8 Signaling Prevents Developmental Exhaustion of the Adult Neural Stem Cell Pool.

Author information

1
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Institute for Cellular Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4
Hugo Moser Research Institute at Kennedy Krieger, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Institute for Cellular Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Saint John's School, Houston, TX 77019, USA.
6
Cardiovascular Research Institute, Department of Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, CA 94158, USA.
7
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shongjun@pennmedicine.upenn.edu.

Abstract

Adult neurogenesis, arising from quiescent radial-glia-like neural stem cells (RGLs), occurs throughout life in the dentate gyrus. How neural stem cells are maintained throughout development to sustain adult mammalian neurogenesis is not well understood. Here, we show that milk fat globule-epidermal growth factor (EGF) 8 (Mfge8), a known phagocytosis factor, is highly enriched in quiescent RGLs in the dentate gyrus. Mfge8-null mice exhibit decreased adult dentate neurogenesis, and furthermore, adult RGL-specific deletion of Mfge8 leads to RGL overactivation and depletion. Similarly, loss of Mfge8 promotes RGL activation in the early postnatal dentate gyrus, resulting in a decreased number of label-retaining RGLs in adulthood. Mechanistically, loss of Mfge8 elevates mTOR1 signaling in RGLs, inhibition of which by rapamycin returns RGLs to quiescence. Together, our study identifies a neural-stem-cell-enriched niche factor that maintains quiescence and prevents developmental exhaustion of neural stem cells to sustain continuous neurogenesis in the adult mammalian brain.

KEYWORDS:

Mfge8; PTEN; RGL; adult neural stem cells; hippocampus; mTOR; neurogenesis; quiescence

PMID:
30174295
PMCID:
PMC6128767
[Available on 2019-09-06]
DOI:
10.1016/j.stem.2018.08.005

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