Summary Neurogenesis continues throughout adulthood in the brains of many animals, including some insects[1–3], and relies on the presence of mitotic neural stem cells. However, in mammals, unlike the liver or skin, the regenerative capacity of the adult nervous system is extremely limited. Using the Drosophila brain as a model, we investigate the mechanisms that restrict adult neurogenesis, with the eventual goal of devising ways to replace neurons lost by injury or disease. We find that in Drosophila, adult neurogenesis is absent due to the elimination of neural stem cells (neuroblasts) during development by cell death. Prior to their elimination, neuroblasts undergo a developmentally regulated reduction in their growth and proliferation rates due to downregulation of insulin/PI3 kinase signaling, resulting in increased levels of nuclear Foxo. These small, growth-impaired neuroblasts are often eliminated by caspase-dependent cell death and not exclusively by terminal differentiation as has been previously proposed[4]. Eliminating Foxo, together with inhibition of pro-apoptotic proteins promotes long-term survival of neuroblasts and sustained neurogenesis in the adult mushroom body (mb), the center for learning and memory in Drosophila. Foxo likely activates an autophagic cell death response, since simultaneous inhibition of ATG1 (autophagy-specific gene 1) and apoptosis also promotes long-term mb neuroblast survival. mb neurons generated in the adult incorporate into the existing mb neuropil suggesting that both neuroblast identity and neuronal pathfinding cues are intact. Thus neurogenesis can be induced in adults by antagonizing pathways that normally function to eliminate neural stem cells during development.
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