Interactions between cells and the environment are essential for stimulating normal migration and inhibiting aberrant migration. How the signaling between cells and the environment instructs migration must be understood before attempting to use stem cells and their progeny for replacement therapeutics. The adult brain subventricular zone (SVZ) contains nestin-positive stem and progenitor cells that give rise to doublecortin (Dcx)-positive neuroblasts, which in turn migrate long-distances to the olfactory bulbs. SVZ cells emigrate to adjacent nuclei in several models of brain injury and disease. The relative control of SVZ migration by intrinsic versus environmental signals is unknown. In all of our specific aims, we will use well characterized cortical aspiration and hypoxia/ischemia lesions, which cause SVZ emigration towards the cerebral cortex and the striatum, respectively. S.A. 1. Test the hypothesis that both intrinsic and environmental signals cause SVZ emigration in adult after brain injury with cross-transplantation. We have evidence that nestin-positive SVZ cells also migrate in the adult SVZ, therefore we will compare nestin-GFP and Dcx-GFP transgenic mice to examine migrating SVZ cell subpopulations. S.A. 2. Determine migration patterns of nestin+ and Dcx+ SVZ cells towards injury with multiphoton videomicroscopy. Though Dcx regulates mammalian cortical development and is specifically expressed by migrating SVZ neuroblasts, whether it is necessary for SVZ migration and emigration is unknown. S.A. 3. Test the hypothesis that Dcx is necessary for emigration of SVZ cells towards brain injury by knocking it down with RNAi. The specific aims are designed to be complementary and to also have intrinsic importance. They will further our understanding of general rules as well as of a candidate gene that governs different SVZ cell subtype migration and are predicted to yield information on autologous brain repair in traumatic brain injury and stroke. [unreadable] [unreadable]