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Neuron. 2014 Sep 3;83(5):1085-97. doi: 10.1016/j.neuron.2014.08.004.

A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells.

Author information

1
Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
2
Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK. Electronic address: nurban@nimr.mrc.ac.uk.
3
Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA.
4
Department for Cell and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden.
5
Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK. Electronic address: fguille@nimr.mrc.ac.uk.

Abstract

The 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.

PMID:
25189209
PMCID:
PMC4157576
DOI:
10.1016/j.neuron.2014.08.004
[Indexed for MEDLINE]
Free PMC Article

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