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 reactivated1-5. 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 neuroblasts6-9 undergo quiescence in a stereotypical spatiotemporal pattern10. Entry into quiescence is regulated by Hox proteins and an internal neuroblast timer11-13. 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 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 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 size16-18 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.

Control of metabolic adaptation to fasting by dILP6-induced insulin signaling in Drosophila oenocytes

“…The role of oenocytes in metabolic adaptation resembles the function of the mammalian liver, as has been predicted from studies in larvae (14). The various insulin-like peptides of flies influence growth and stress responses in different contexts, providing a complex, spatiotemporally defined regulatory system to sustain local cell growth, proliferation, cell survival, and metabolism (10,11,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). So far, the molecular codes that ensure specificity in this signaling network remain unclear.…”

“…In Drosophila, IIS activity is stimulated by a number of different insulin-like peptides (ILPs) that are independently regulated and can act in endocrine as well as local, paracrine fashion. A major source of dILPs are the median neurosecretory cells (mNSCs, also known as insulin-producing cells, IPCs) in the pars intercerebralis of the head, but expression of individual dILPs has also been reported in the gut, the ovary, glial cells, fat body, and abnormally growing imaginal discs (10,11,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Whereas secretion of dILP2, -3, and -5 from mNSCs is regulated by nutritional cues, transcriptional regulation of these peptides depends on the stimulus (9,21).…”

Cross-talk between the fat body and brain regulates insect developmental arrest

“…Work with Drosophila indicates that the fat body affects growth and development by regulating synthesis and release of the neurohormone insulin from the brain (14,15), and our experiments with H. armigera show that the fat body can exert an effect on the brain regulatory center by altering sugar levels and levels of TCA metabolites. Injection of ecdysteroids can artificially break diapause, a response accompanied by elevation of COX activity and ATP content in the fat body as noted (Fig.…”

“…For example, diapause in members of the Heliothis/Helicoverpa complex can also be terminated by the neuropeptide diapause hormone (1, 16, 17), but we do not yet know how diapause hormone or other regulatory molecules, such as insulin (14,15), may be linked to the scheme presented in Fig. 3C.…”

Control of neural stem cell self-renewal and differentiation in Drosophila

“…Through the insulin receptor (InR), Dilp activates the PI3K/AKTTarget of Rapamaycin (TOR) signaling pathway in neuroblasts and this, in turn, induces the neuroblasts to exit quiescence, increase volume, and re-enter the cell cycle. (Chell and Brand, 2010;Shim et al, 2013;Sousa-Nunes et al, 2011). In contrast to the neuroblasts that undergo quiescence and reactivation, in the abdominal ganglia many of the embryonic neuroblasts are eliminated at late embryogenesis through programmed cell death !…”