OLIGODENDROCYTE LINEAGE GENE FUNCTION IN THE CNS

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In preliminary studies, we have cloned and characterized a pair of Oligodendrocyte lineage genes (Olg) that encode a novel class of bHLH proteins. Human OLG-1 and OLG-2 co-localize within 50 kb of each other n the Down's Syndrome critical region. Olg genes are expressed exclusively within the central nervous system (CNS) of rodents. Olg expression overlaps, but precedes, the earliest known markers of oligodendrocyte development. Moreover, in cell culture, virus-mediated ectopic expression of 0lg-1 directs multipotent cortical progenitor cells to express early markers of the oligodendroycte lineage. The studies described here build upon this work. We have four specific aims: Aim 1 is to determine whether 0lg gene expression is sufficient to initiate the formation of oligodendrocytes in animals. We will use a bigenic system to achieve conditional expression of wild type and mutated 0lg genes in developing neural tube of transgenic mice. Aim 2 is to determine whether Olg gene expression is necessary for oligodendrocyte development. We will use a slightly unusual method to generate classical knockouts of of 0lg-1 and 0lg-2. We will disrupt the genes by targeted insertion of lacZ and Cre recombinase genes, respectively. The mouse strains that we create in this way will be useful for additional experiments (see specific aim 3 below) even if there is no discernable phenotype in the 0lg knockouts. Aim 3 is to determine whether 0lg genes function exclusively in formation of oligodendrocytes. We will map the long-term fate of neural progenitor cells that have expressed 0lg genes by mating the 0lg/Cre knockout mice (Aim 2) to a "Floxed" betageo conditional reporter mouse strain. Aim 4 is to define the molecular functions of 0lg gene products within multipotent neural progenitor cells. We will focus on roles in transcriptional regulation and characterize structural features required for functional activity. Insights into 0lg gene functions derived from these studies could impact a broad range of disease states involving myelin-producing cells of the CNS. In particular, the work may shed light on the molecular phenotype of glial tumors and point to possible new therapies.