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. 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. It is unknown if injury causes changes in intrinsic factors in SVZ cells that are sufficient to drive their emigration. SA 1. Test the hypothesis that intrinsic factors are sufficient to cause SVZ emigration in adult after brain injury. 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 emigrating SVZ cell subpopulations. SA 2. Determine migration patterns of nestin+ and Dcx+ SVZ cells towards injury with mutiphoton 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 and will be determined with RNAi. SA 3. Test the hypothesis that Dcx is necessary for SVZ emigration towards brain injury. Laminin/ alpha6/beta1 integrin signaling is necessary for normal SVZ migration, but whether it is required for their emigration after injury is unknown. SA. 4. Test the hypothesis that Iaminin/a6b1 integrin signaling is necessary for SVZ emigration towards brain injury.
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 candidate molecules that govern different SVZ cell subtype emigration after injury and are predicted to yield information on autologous brain repair in traumatic brain injury and stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Owens, David F
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University of Oxford
United Kingdom
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OX1 2-JD
Kim, Yongsoo; Wang, Wei-Zhi; Comte, Isabelle et al. (2010) Dopamine stimulation of postnatal murine subventricular zone neurogenesis via the D3 receptor. J Neurochem 114:750-60