MECHANISMS OF REGULATING ASTROGLIAL LINEAGE DEVELOPMENT

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DESCRIPTION: Using epidermal growth factor (EGF)-derived embryonic subventricular zone (SVZ) multipotent neural progenitor cells, we have identified a subclass of the transforming growth factor b (TGFb) superfamily, the bone morphogenetic proteins (BMPs), that mediate the selective, dose-dependent elaboration of astrocytes, with concurrent suppression of neuronal and oligodendroglial lineage development. Transcripts and proteins for the BMP ligands and BMP type I and II receptor subunits are present in brain and SVZ progenitor cells at the appropriate times to mediate these trophic actions. In concert with activation of the LIFb receptor, BMPs and bFGF potentiate the early expression of radial glia, with later enhancement (BMP) or inhibition (bFGF) of the astroglial phenotype. These observations suggest that the BMPs represent a new class of signaling molecules that may regulate astroglial lineage commitment and may interact with distinct early signaling molecules. The general hypothesis underlying this proposal is that the BMPs are instructive signals that regulate astroglial lineage commitment, and that regulation of BMP receptor subunits and/or BMP ligands determine the pattern of astrocyte lineage elaboration during brain development: A. Clonal and single cell analysis will be utilized to determine whether the BMP astroglial-promoting effects constitute instructive cellular signals, whether different BMPs suppress the neuronal and oligodendroglial lineages and whether progenitor cell responsiveness to the BMPs in vitro correlates with changes in BMP receptor expression. B. Isolated EGF-responsive progenitor cells and tissue sections from sequential stages of gliogenesis will be examined to define changes in the degree of BMP-progenitor cell responsiveness, the profile of astroglial lineage species, and alterations in the spatiotemporal expression of BMP receptors and ligands to establish in vitro-in vivo correlations. C. The role of LIF and bFGF in modulating the BMP-mediated expression and cellular responsiveness of radial glial populations will be studied to determine whether these cellular changes reflect opposing effects on BMP receptor expression. These studies will further our understanding of the epigenetic signals and cellular mechanisms that regulate the development of the astroglial lineage. Because many of the cellular processes present during astroglial development may be recapitulated during pathological states, these findings may also have important implications for our understanding of glial-mediated responses in traumatic injury, demyelinating disorders and mammalian central nervous system cellular transformation.