A Transcriptional Mechanism Integrating Inputs from Extracellular Signals to Activate Hippocampal Stem Cells

Jimena Andersen,Noelia Urbán,Angeliki Achimastou,Ayako Ito,Milesa Simic,Kristy Ullom,Ben Martynoga,Mélanie Lebel,Christian Göritz,Jonas Frisén,Masato Nakafuku,François Guillemot

doi:10.1016/j.neuron.2014.08.004

Jimena Andersen, Noelia Urbán + Show 10 more

Open Access

https://doi.org/10.1016/j.neuron.2014.08.004

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Abstract

SummaryThe activity of adult stem cells is regulated by signals emanating from the surrounding tissue. Many niche signals have been identified, but it is unclear how they influence the choice of stem cells to remain quiescent or divide. Here we show that when stem cells of the adult hippocampus receive activating signals, they first induce the expression of the transcription factor Ascl1 and only subsequently exit quiescence. Moreover, lowering Ascl1 expression reduces the proliferation rate of hippocampal stem cells, and inactivating Ascl1 blocks quiescence exit completely, rendering them unresponsive to activating stimuli. Ascl1 promotes the proliferation of hippocampal stem cells by directly regulating the expression of cell-cycle regulatory genes. Ascl1 is similarly required for stem cell activation in the adult subventricular zone. Our results support a model whereby Ascl1 integrates inputs from both stimulatory and inhibitory signals and converts them into a transcriptional program activating adult neural stem cells.

Highlights

Adult stem cells maintain tissue function and integrity throughout the lifetime of an organism
Ascl1 Is Expressed by Activated Stem Cells in the Adult Hippocampus To study the function of Ascl1 in hippocampal neurogenesis, we first characterized its expression in the adult hippocampus
Labeling of 2-month-old mouse brains with a monoclonal antibody against Ascl1 showed that in the hippocampus, Ascl1-expressing cells are restricted to the subgranular zone (SGZ) of the dentate gyrus (DG) (Figure 1A)

Summary

Introduction

Adult stem cells maintain tissue function and integrity throughout the lifetime of an organism. Niche signals might act by inducing the expression or activity of transcription factors that in turn regulate the large number of genes differentially expressed between quiescent and active stem cells (Lien et al, 2011; Martynoga et al, 2013; Venezia et al, 2004). Transcription factors have been shown to regulate stem cell activity in various tissues by controlling their proliferation, survival, or differentiation (Akala and Clarke, 2006; Goldstein and Horsley, 2012). It is not known in most instances how these factors are regulated (Niu et al, 2011; Osorio et al, 2008)

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