Hedgehog signalling and lipid metabolism in glia regulate neural stem cell proliferation in Drosophila

Summary The final size of the adult central nervous system (CNS) is determined by the size of neuronal lineages generated by neural stem cells (NSCs) during development. In Drosophila, NSCs called neuroblasts (NBs) reside within a specialised microenvironment called the glial niche. Here, we explore non-cell autonomous regulation of NB behaviour by glia during normal development, and upon glial overgrowth. We show that lipid droplets that reside within the glial niche are closely associated with the signalling molecule Hedgehog (Hh). Under physiological conditions, Hh is present at low levels in the glial niche to ensure NBs faithfully produce the correct number and types of progeny that populate the adult nervous system. Upon Fibroblast Growth Factor (FGF) activation in glia, an accumulation of lipid droplets and Hh ligand non-cell autonomously triggers adjacent NBs to reduce their cell cycle speed, increase the developmental period in which they proliferate and disrupt their asymmetric division. Downstream of FGF signalling in the glia, we found that lipid metabolism affects both Hh subcellular localisation, as well as Hh post-translational modification, to modulate its activity, and in turn, its ability to activate Hh-signalling in the adjacent NBs. Together, our data suggest that wildtype and dysfunctional glial niche non-autonomously regulate neural lineage size via modulation of lipid metabolism and Hedgehog signalling.