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

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 (CNS), 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 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 the FDS, Insulin-like receptor (InR) 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 hemolymph by median neurosecretory cells (mNSCs) systemically control organismal size(16-18) but do not reactivate neuroblasts. Drosophila thus contains two segregated Ilp pools, one regulating proliferation within the CNS and the other controlling tissue growth systemically. Together, 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 highlights that dietary nutrients and remote organs, as well as local niches, are key regulators of transitions in stem-cell behaviour.