Abstract
Many stem, progenitor and cancer cells undergo periods of mitotic quiescence from which they can be reactivated1,2,3,4,5. The signals triggering entry into and exit from this reversible dormant state are not well understood. In the developing Drosophila central nervous system, multipotent self-renewing progenitors called neuroblasts6,7,8,9 undergo quiescence in a stereotypical spatiotemporal pattern10. Entry into quiescence is regulated by Hox proteins and an internal neuroblast timer11,12,13. Exit from quiescence (reactivation) is subject to a nutritional checkpoint requiring dietary amino acids14. Organ co-cultures also implicate an unidentified signal from an adipose/hepatic-like tissue called the fat body14. Here we provide in vivo evidence that Slimfast amino-acid sensing and Target of rapamycin (TOR) signalling15 activate a fat-body-derived signal (FDS) required for neuroblast reactivation. Downstream of this signal, Insulin-like receptor signalling and the Phosphatidylinositol 3-kinase (PI3K)/TOR network are required in neuroblasts for exit from quiescence. We demonstrate that nutritionally regulated glial cells provide the source of Insulin-like peptides (ILPs) relevant for timely neuroblast reactivation but not for overall larval growth. Conversely, ILPs secreted into the haemolymph by median neurosecretory cells systemically control organismal size16,17,18 but do not reactivate neuroblasts. Drosophila thus contains two segregated ILP pools, one regulating proliferation within the central nervous system and the other controlling tissue growth systemically. Our findings support a model in which amino acids trigger the cell cycle re-entry of neural progenitors via a fat-body–glia–neuroblasts relay. This mechanism indicates that dietary nutrients and remote organs, as well as local niches, are key regulators of transitions in stem-cell behaviour.
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Acknowledgements
We are grateful to A. Brand, S. Cohen, B. Edgar, U. Gaul, E. Hafen, C. Klambt, T. Lee, S. Leevers, P. Leopold, F. Matsuzaki, I. Miguel-Aliaga, T. Neufeld, R. Palmer, L. Partridge, L. Pick, E. Sanchez-Herrero, H. Stocker, N. Tapon and T. Xu, and also to the Bloomington stock centre and Kyoto National Institute of Genetics (NIG) for Drosophila stocks, antibodies and plasmids. We also acknowledge I. Salecker, J.-P. Vincent, A. Bailey, E. Cinnamon, L. Cheng, R. Makki, A. Matheu, P. Pachnis, P. Serpente and I. Stefana for providing advice, reagents and critical reading of the manuscript. The authors were supported by the Medical Research Council (U117584237).
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R.S.-N. and A.P.G. designed the experiments, R.S.-N. and L.L.Y. performed the experiments and R.S.-N. and A.P.G. wrote the manuscript. All authors have read and subscribe to the contents of the manuscript.
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Sousa-Nunes, R., Yee, L. & Gould, A. Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila. Nature 471, 508–512 (2011). https://doi.org/10.1038/nature09867
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DOI: https://doi.org/10.1038/nature09867
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