Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila

TY - JOUR

T1 - Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila

AU - Sousa-Nunes, Rita

AU - Yee, Lih Ling

AU - Gould, Alex P.

PY - 2011/3/24

Y1 - 2011/3/24

N2 - Many stem, progenitor and cancer cells undergo periods of mitotic quiescence from which they can be reactivated(1-5). 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 neuroblasts(6-9) undergo quiescence in a stereotypical spatiotemporal pattern(10). Entry into quiescence is regulated by Hox proteins and an internal neuroblast timer(11-13). Exit from quiescence (reactivation) is subject to a nutritional checkpoint requiring dietary amino acids(14). Organ co-cultures also implicate an unidentified signal from an adipose/hepatic-like tissue called the fat body(14). Here we provide in vivo evidence that Slimfast amino-acid sensing and Target of rapamycin (TOR) signalling(15) 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 size(16-18) 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.

AB - Many stem, progenitor and cancer cells undergo periods of mitotic quiescence from which they can be reactivated(1-5). 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 neuroblasts(6-9) undergo quiescence in a stereotypical spatiotemporal pattern(10). Entry into quiescence is regulated by Hox proteins and an internal neuroblast timer(11-13). Exit from quiescence (reactivation) is subject to a nutritional checkpoint requiring dietary amino acids(14). Organ co-cultures also implicate an unidentified signal from an adipose/hepatic-like tissue called the fat body(14). Here we provide in vivo evidence that Slimfast amino-acid sensing and Target of rapamycin (TOR) signalling(15) 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 size(16-18) 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.

U2 - 10.1038/nature09867

DO - 10.1038/nature09867

M3 - Article

SN - 0028-0836

VL - 471

SP - 508

EP - 512

JO - NATURE

JF - NATURE

IS - 7339

ER -