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

Abstract

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.