Neural precursors have long been of interest to developmental biologists. These cells have recently gained the interest of the broader neuroscience community because of their involvement in olfaction, learning and memory, cognitive decline with aging and their potential to replace neurons or glial cells that have died as a consequence of brain injury or disease. The cells that are of significant interest are the neural stem cells (NSCs). These cells naturally reside within specific niches where they receive signals that are necessary to maintain them in a primitive state. To date, the possibility that IGF-II is a necessary component of the stem cell niche has not been considered largely because IGF-II has been regarded as a fetal growth factor. However, IGF-II is expressed at high levels within the choroid plexus, which produces the cerebrospinal fluid that is readily accessible to the NSCs because they extend a process directly into the ventricle that is bathed by cerebrospinal fluid. Whereas both IGF-II and IGF-I activate the IGF type 1 receptor (IGF-1R), IGF-II also binds to a splice variant isoform of the insulin receptor (IR-A) supporting distinct roles for IGF-II versus IGF-I. The overall hypothesis of this proposal is that IGF-II is essential for NSC self-renewal, maintenance and growth through the insulin receptor. Our overall hypothesis will be tested using inducible Cre driver lines to achieve both temporal discrete deletion of IGF-II or insulin receptors. Studies will be performed at the molecular, cellular and behavioral levels. Identifying IGF-II as necessary to sustain NSCs as primitive cells will be a significant scientific advance. Moreover, establishing which signaling receptor and downstream transcription factors are activated by this signal might well provide insights into new strategies to amplify these important cells to promote brain growth, maintain cell replacement across the lifespan and enhance cell replacement in the diseased or damaged brain. IGF-II is also expressed in other organs where there are adult stem cells, yet a role for IGF-II in adult stem cell maintenance has not been explored in mammalian tissues. Therefore, upon completing the proposed experiments we will be uniquely positioned to submit an R01 application to investigate these important and timely issues.