title: A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells.
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.
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Jimena
authors.initials: J
authors.lastname: Andersen
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK. Electronic address: nurban@nimr.mrc.ac.uk.
authors.forename: Noelia
authors.initials: N
authors.lastname: Urbán
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Achimastou
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Ayako
authors.initials: A
authors.lastname: Ito
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA.
authors.forename: Milesa
authors.initials: M
authors.lastname: Simic
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Ullom
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Martynoga
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Lebel
authors.affiliation: Department for Cell and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Göritz
authors.affiliation: Department for Cell and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Frisén
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229-3039, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakafuku
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK. Electronic address: fguille@nimr.mrc.ac.uk.
authors.forename: François
authors.initials: F
authors.lastname: Guillemot
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002552:Cerebral Ventricles / Q000166:cytology; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000235:genetics; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics*; D020825:T-Box Domain Proteins / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D027341:Excitatory Amino Acid Transporter 1; D005904:Glial Fibrillary Acidic Protein; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D056484:Jumonji Domain-Containing Histone Demethylases; D007608:Kainic Acid; D020825:T-Box Domain Proteins; D050880:p300-CBP Transcription Factors; C499317:Ascl1 protein, mouse; C491198:Eomes protein, mouse; C493393:Slc1a3 protein, mouse; C523761:Kdm6b protein, mouse