Inactivation of Both foxo and reaper Promotes Long-Term Adult Neurogenesis in Drosophila

Abstract

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.

Drosophila neuroblasts: a model for stem cell biology

“…Mushroom body NBs, which are the last ones to disappear, first decrease their proliferation in response to a decrease in insulin/PI3K signaling that occurs in the fasting pupal stages. This results in nuclear localization of the transcription factor Foxo (Forkhead box class O) followed by Reaper-dependent apoptosis and autophagy of these NBs (Siegrist et al, 2010). Abdominal VNC NBs undergo apoptosis in response to a pulse of the Hox gene abdominal A (White et al, 1994;Bello et al, 2003).…”

Neuroblast niche position is controlled by PI3-kinase dependent DE-Cadherin adhesion

“…In these animals (designated as p35 animals), in which NB apoptosis is blocked, we observed MB NBs located on the dorsal surface superficial to the MB calyces in brains of 1-day-old adults ( Fig. 1A, top; quantified in 1D) (Siegrist et al, 2010). In addition, other cells expressing the NB transcription factor Deadpan (Dpn) were also observed in an anterior-medial brain region known as the pars intercerebralis (PI) (Fig.…”

“…Activation of PI3-kinase not only reactivates quiescent NBs, but also maintains NB proliferation rates throughout development, ensuring sufficient numbers of neurons and glia are produced for adult brain function. Levels of PI3-kinase activity remain high in NBs during development, but decrease in MB NBs prior to termination of neurogenesis (Siegrist et al, 2010). Decreasing levels of PI3-kinase activity in MB NBs ensures that MB NBs terminate cell divisions on time and prevents excess MB neurogenesis, which could be deleterious (Siegrist et al, 2010).…”

“…Central brain NBs are specified during embryogenesis, proliferate throughout most of larval development, and terminate cell divisions during pupal stages before adult formation. All central brain NBs terminate cell divisions within 30 h after pupal formation, except for the eight mushroom body (MB) NBs (four per brain lobe, eight total) (Truman and Bate, 1988;Ito and Hotta, 1992;Siegrist et al, 2010). These NBs persist late and undergo apoptosis only shortly before animals emerge from their pupal case as young adults (Truman and Bate, 1988;Ito and Hotta, 1992;Siegrist et al, 2010).…”

FOXO Transcription Factors as Potential Therapeutic Targets in Neuroblastoma

“…Adult neurogenesis relies on adult mitotic neural stem cells. Activation of dFOXO in Drosophila causes the elimination of these neural stem cells during the development via Caspase-dependent cell death (Siegrist et al, 2010). In adult neural stem cells that lack FOXO1, FOXO3 and FOXO4 due to gene deletion, increased levels of reactive oxygen species (ROS) are detected.…”