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PMID: 20943920 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

RBPJkappa-dependent signaling is essential for long-term maintenance of neural stem cells in the adult hippocampus.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 30 ·No. 41 ·2010-10-13 ·Pages 13794-807

Ehm O, Göritz C, Covic M, Schäffner I, Schwarz TJ, Karaca E, Kempkes B, Kremmer E, Pfrieger FW, Espinosa L, Bigas A, Giachino C, Taylor V, Frisén J, Lie DC

Abstract

The generation of new neurons from neural stem cells in the adult hippocampal dentate gyrus contributes to learning and mood regulation. To sustain hippocampal neurogenesis throughout life, maintenance of the neural stem cell pool has to be tightly controlled. We found that the Notch/RBPJκ-signaling pathway is highly active in neural stem cells of the adult mouse hippocampus. Conditional inactivation of RBPJκ in neural stem cells in vivo resulted in increased neuronal differentiation of neural stem cells in the adult hippocampus at an early time point and depletion of the Sox2-positive neural stem cell pool and suppression of hippocampal neurogenesis at a later time point. Moreover, RBPJκ-deficient neural stem cells displayed impaired self-renewal in vitro and loss of expression of the transcription factor Sox2. Interestingly, we found that Notch signaling increases Sox2 promoter activity and Sox2 expression in adult neural stem cells. In addition, activated Notch and RBPJκ were highly enriched on the Sox2 promoter in adult hippocampal neural stem cells, thus identifying Sox2 as a direct target of Notch/RBPJκ signaling. Finally, we found that overexpression of Sox2 can rescue the self-renewal defect in RBPJκ-deficient neural stem cells. These results identify RBPJκ-dependent pathways as essential regulators of adult neural stem cell maintenance and suggest that the actions of RBPJκ are, at least in part, mediated by control of Sox2 expression.

MeSH Terms
Adult Stem Cells/metabolism Animals Blotting, Western Cell Count Chromatin Immunoprecipitation Female Hippocampus/metabolism Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics,metabolism Male Mice Mice, Transgenic Microscopy, Confocal Neurogenesis/physiology Neurons/metabolism Receptors, Notch/metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/physiology Statistics, Nonparametric
Chemicals
Immunoglobulin J Recombination Signal Sequence-Binding Protein Rbpj protein, mouse Receptors, Notch
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Ehm Oliver
Research Group Adult Neurogenesis and Neural Stem Cells, Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.
Göritz Christian
Covic Marcela
Schäffner Iris
Schwarz Tobias J
Karaca Esra
Kempkes Bettina
Kremmer Elisabeth
Pfrieger Frank W
Espinosa Lluis
Bigas Anna
Giachino Claudio
Taylor Verdon
Frisén Jonas
Lie D Chichung
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1567-10.2010
Published
2010-10-13
Pages
13794-807
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6633732
Subset
IM
External Links
PubMed source DOI: 10.1523/JNEUROSCI.1567-10.2010 PMC Full Text View journal details
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