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Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence.

Accepted version
Peer-reviewed

Type

Article

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Abstract

Quiescent stem cells in adult tissues can be activated for homeostasis or repair. Neural stem cells (NSCs) in Drosophila are reactivated from quiescence in response to nutrition by the insulin signaling pathway. It is widely accepted that quiescent stem cells are arrested in G0 In this study, however, we demonstrate that quiescent NSCs (qNSCs) are arrested in either G2 or G0 G2-G0 heterogeneity directs NSC behavior: G2 qNSCs reactivate before G0 qNSCs. In addition, we show that the evolutionarily conserved pseudokinase Tribbles (Trbl) induces G2 NSCs to enter quiescence by promoting degradation of Cdc25String and that it subsequently maintains quiescence by inhibiting Akt activation. Insulin signaling overrides repression of Akt and silences trbl transcription, allowing NSCs to exit quiescence. Our results have implications for identifying and manipulating quiescent stem cells for regenerative purposes.

Description

Keywords

Animals, Cell Cycle, Cell Cycle Proteins, Drosophila Proteins, Drosophila melanogaster, Insulin, Neural Stem Cells, Neurogenesis, Protein Serine-Threonine Kinases, Protein Tyrosine Phosphatases, Proteolysis, Proto-Oncogene Proteins c-akt, Regeneration, Signal Transduction, Time Factors

Journal Title

Science

Conference Name

Journal ISSN

0036-8075
1095-9203

Volume Title

360

Publisher

American Association for the Advancement of Science (AAAS)
Sponsorship
Wellcome Trust (092545/Z/10/Z)
Wellcome Trust (103792/Z/14/Z)
Royal Society (RP150061)
Wellcome Trust (097423/Z/11/Z)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
This work was funded by the Royal Society Darwin Trust Research Professorship, Wellcome Trust Senior Investigator Award 103792 and Wellcome Trust Programme grant 092545 to A.H.B., and Wellcome Trust PhD Studentship 097423 to L.O. A.H.B acknowledges core funding to the Gurdon Institute from the Wellcome Trust (092096) and CRUK (C6946/A14492).