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Inactivation of both Foxo and reaper promotes long-term adult neurogenesis in Drosophila.

ABSTRACT: Adult neurogenesis occurs in specific locations in the brains of many animals, including some insects, and relies on mitotic neural stem cells. In mammals, the regenerative capacity of most of the adult nervous system is extremely limited, possibly because of the absence of neural stem cells. Here we show that the absence of adult neurogenesis in Drosophila results from the elimination of neural stem cells (neuroblasts) during development. Prior to their elimination, their growth and proliferation slows because of decreased insulin/PI3 kinase signaling, resulting in nuclear localization of Foxo. These small neuroblasts are typically eliminated by caspase-dependent cell death, and not exclusively by terminal differentiation as has been proposed. Eliminating Foxo, together with inhibition of reaper family proapoptotic genes, promotes long-term survival of neuroblasts and sustains neurogenesis in the adult mushroom body (mb), the center for learning and memory in Drosophila. Foxo likely activates autophagic cell death, because simultaneous inhibition of ATG1 (autophagy-specific gene 1) and apoptosis also promotes long-term mb neuroblast survival. mb neurons generated in adults incorporate into the existing mb neuropil, suggesting that their identity and neuronal pathfinding cues are both intact. Thus, inhibition of the pathways that normally function to eliminate neural stem cells during development enables adult neurogenesis.

SUBMITTER: Siegrist SE

PROVIDER: S-EPMC2862284 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Inactivation of both Foxo and reaper promotes long-term adult neurogenesis in Drosophila.

Siegrist Sarah E SE Haque Najm S NS Chen Chun-Hong CH Hay Bruce A BA Hariharan Iswar K IK

Current biology : CB 20100325 7

Adult neurogenesis occurs in specific locations in the brains of many animals, including some insects, and relies on mitotic neural stem cells. In mammals, the regenerative capacity of most of the adult nervous system is extremely limited, possibly because of the absence of neural stem cells. Here we show that the absence of adult neurogenesis in Drosophila results from the elimination of neural stem cells (neuroblasts) during development. Prior to their elimination, their growth and proliferati ...[more]

PMID: 20346676

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Project description:Stroke increases neurogenesis in the adult dentate gyrus in the short term, however, long-term effects at the cellular and functional level are poorly understood. Here we evaluated the impact of an early stroke lesion on neurogenesis and cognitive function of the aging brain. We hypothesized that a stroke disturbs dentate neurogenesis during aging correlate with impaired flexible learning. To address this issue a stroke was induced in 3-month-old C57Bl/6 mice by a middle cerebral artery occlusion (MCAO). To verify long-term changes of adult neurogenesis the thymidine analogue BrdU (5-Bromo-2'-deoxyuridine) was administrated at different time points during aging. One and half months after BrdU injections learning and memory performance were assessed with a modified version of the Morris water maze (MWM) that includes the re-learning paradigm, as well as hippocampus-dependent and -independent search strategies. After MWM performance mice were transcardially perfused. To further evaluate in detail the stroke-mediated changes on stem- and progenitor cells as well as endogenous proliferation nestin-green-fluorescent protein (GFP) mice were used. Adult nestin-GFP mice received a retroviral vector injection in the hippocampus to evaluate changes in the neuronal morphology. At an age of 20 month the nestin-GFP mice were transcardially perfused after MWM performance and BrdU application 1.5 months later. The early stroke lesion significantly decreased neurogenesis in 7.5- and 9-month-old animals and also endogenous proliferation in the latter group. Furthermore, immature doublecortin (DCX)-positive neurons were reduced in 20-month-old nestin-GFP mice after lesion. All MCAO groups showed an impaired performance in the MWM and mostly relied on hippocampal-independent search strategies. These findings indicate that an early ischemic insult leads to a dramatical decline of neurogenesis during aging that correlates with a premature development of hippocampal-dependent deficits. Our study supports the notion that an early stroke might lead to long-term cognitive deficits as observed in human patients after lesion.

Dataset Information

Inactivation of both Foxo and reaper promotes long-term adult neurogenesis in Drosophila.

Publications

Inactivation of both Foxo and reaper promotes long-term adult neurogenesis in Drosophila.

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