Regulation of neurogenesis termination during development

A remarkable number of morphologically and functionally diverse neurons and glia make up the brain. All of these neurons are generated by the highly regulated asymmetric cell divisions of populations of neural stem cells, which are multi-potent self-renewing progenitors. As development approaches completion, neurogenesis becomes limited in some adult animals due in part to the depletion of neural stem cells. Restricting neurogenesis during development may protect the functioning of the adult brain as ectopic proliferation of neural stem cells can disrupt neural circuitry or act as seeds for tumorigenesis. To date, the molecular mechanisms that terminate cell divisions of neural stem cells are poorly understood.

Here, I describe our work characterizing factors that regulate the developmentally programmed elimination of a subset of Drosophila neural stem cells, termed neuroblasts, with the goal of understanding how neurogenesis becomes limited during brain development. Eight mushroom body neuroblasts generate the neurons that form the mushroom body, a structure important for some types of memory and learning. The mushroom body neuroblasts are eliminated relatively late in development by a combination of apoptosis and autophagy in late pupal stages.

We first examined the regulation of apoptosis in terminating MB neuroblast divisions. To identify genes that regulate the elimination of the MB neuroblasts, we conducted a directed RNAi screen to find cell-intrinsic regulators of MB neuroblast termination. From this screen, we identified multiple genes are required for the elimination of Drosophila neuroblasts.

We further characterized one gene identified from our screen, the steroid hormone-induced transcription factor E93, which down regulates PI3-kinase to activate autophagy for MB neuroblast elimination. Expression of E93 is restricted to late-staged MB neuroblasts by cell-intrinsic temporal factors. We found evidence that systemic ecdysone signaling increases E93 levels for termination. Altogether, E93 functions as a late-acting temporal factor that integrates extrinsic hormonal developmental timing cues with neuroblast intrinsic temporal state to precisely time the termination of neurogenesis during development.