Our laboratory has been examining the genesis of astrocytes and oligodendrocytes during early CNS development and the nature and differentiation potential of immature glial cells in the adult CNS. We propose to continue a series of studies that include: 1. Further examination of early gliogenesis. a. We will continue to examine early stages of astrocyte development in vivo by looking for the concurrent expression of astrocyte genes and the contact between progenitors and blood vessels in the developing neocortex. We will also continue our real-time video imaging of migrating progenitors to examine the early stages of astrocyte development. b. We will ask if interactions between progenitors from the SVZ and endothelial cells induce astrocyte phenotype, co-culturing progenitors from the neonatal SVZ with endothelial cells. c. We will continue to study pathways of progenitor migration. Since our previous data suggests that radial glia represent one of the major pathways along which progenitors from the SVZ migrate into gray matter and white matter, we will try to visualize that interaction directly using retroviral gene transfer into the SVZ of the transgenic mouse that expresses green fluorescent protein driven by the GFAP promoter. d. We will further characterize cycling cells in the neonatal SVZ. 2. We will continue to characterize gliogenesis and neurogenesis in the postnatal cerebellum. a. Are the dividing progenitors in cerebellar white matter multipotent cells or are there separate progenitors for neurons and glia? We will approach this question by performing a series of in vitro and in vivo clonally analyses and by looking for markers that might distinguish neuronal from glial progenitors. b. What are the patterns of migration and cell development in the postnatal cerebellum? We hope to be able to perform video imaging of glial development in cerebellar slices for several days, since such slices can be kept alive for prolonged periods. 3. Further characterization of cycling cells in the adult CNS. We have begun to characterize a population of dividing progenitors in the adult rat subcortical white matter and neocortex, and have shown that some of these cells will differentiate into myelinating oligodendrocytes in response to a local demyelination. We will continue to characterize these cells in several respects to ask what growth factor receptors do these cells express and how do they respond to specific growth factors. b. How do these cycling cells respond to pathological conditions? We are particularly interested in understanding whether such pathologies as demyelination and trauma will cause these progenitors to accumulate, through increased proliferation and/or decreased cell death, as well as how pathologies induce glial differentiation.
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