An important question in stem cell biology is how a cell decides to self-renew or differentiate. Drosophila neuroblasts divide asymmetrically to self-renew and generate differentiating progeny called GMCs. Here, we report that the Brain tumor (Brat) translation repressor is partitioned into GMCs via direct interaction with the Miranda scaffolding protein. In brat mutants, another Miranda cargo protein (Prospero) is not partitioned into GMCs, GMCs fail to downregulate neuroblast gene expression, and there is a massive increase in neuroblast numbers. Single neuroblast clones lacking Prospero have a similar phenotype. We conclude that Brat suppresses neuroblast stem cell self-renewal and promotes neuronal differentiation.

Cortical polarity regulates cell division, migration, and differentiation. Microtubules induce cortical polarity in yeast, but few examples are known in metazoans. We show that astral microtubules, kinesin Khc-73, and Discs large (Dlg) induce cortical polarization of Pins/Galphai in Drosophila neuroblasts; this cortical domain is functional for generating spindle asymmetry, daughter-cell-size asymmetry, and distinct sibling fates. Khc-73 localizes to astral microtubule plus ends, and Dlg/Khc-73 and Dlg/Pins coimmunoprecipitate, suggesting that microtubules induce Pins/Galphai cortical polarity through Dlg/Khc-73 interactions. The microtubule/Khc-73/Dlg pathway acts in parallel to the well-characterized Inscuteable/Par pathway, but each provides unique spatial and temporal information: The Inscuteable/Par pathway initiates at prophase to coordinate neuroblast cortical polarity with CNS tissue polarity, whereas the microtubule/Khc-73/Dlg pathway functions at metaphase to coordinate neuroblast cortical polarity with the mitotic spindle axis. These results identify a role for microtubules in polarizing the neuroblast cortex, a fundamental step for generating cell diversity through asymmetric cell division.

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.