Nutritional control of neural stem cell quiescence and reactivation. (360G-Wellcome-103792_Z_14_Z)

The systemic regulation of stem cells ensures that they meet the needs of the organism during growth and in response to injury. Stem cell populations in tissues as varied as blood, gut, and brain, spend much of their time in a mitotically dormant, quiescent, state. A key point of regulation is the decision between quiescence and proliferation. In the mammalian brain, the neural stem cells in the subventricular zone and hippocampal subgranular zone undergo a transition between quiescence and prol iferation, generating new neurons throughout the life of the animal. The ability to reactivate neural stem cells in situ raises the prospect of potential future therapies for brain repair after damage or neurodegenerative disease. Understanding the molecular basis for stem cell reactivation is an essential first step in this quest. A number of factors have been shown to have mitogenic effects on vertebrate neural stem cells, however it is not clear upon which cells (stem cells or their prolif erative progeny), and at what point in the cell cycle, these factors act. In Drosophila, quiescent neural stem cells are easily identifiable and amenable to genetic manipulation, making them a powerful model with which to study the transition between quiescence and proliferation. These stem cells exit quiescence in response to a nutrition-dependent signal from the fat body, a tissue that plays a key role in the regulation of metabolism and growth. My lab will combine cutting edge genetic and mol ecular approaches with advanced imaging techniques to study the reactivation of Drosophila neural stem cells in vivo. This model system enables us to deduce the sequence of events from the level of the organism, to the tissue, the cell, and finally the genome. The questions we propose to address are: a) How do environmental signals influence neural stem cell behaviour? b) What are these signals and how are they received by the stem cell niche and transmitted to neural stem cells? c) Wh at are the transcriptional and epigenetic changes in neural stem cells in the transition from quiescence to proliferation? d) How similar are quiescent neural stem cells in the adult to those in the developing animal? How are they altered with age? e) How conserved are the molecular mechanisms regulating neural stem cell reactivation in Drosophila and mammals?