Research Description
Highlights of Major Accomplishments
- Discovery that expression of this pair of genes precedes the earliest known markers of oligodendrocyte development and is regulated by Sonic hedgehog.
Major Results
In preliminary collaborative studies with Dr. Charles Stiles of this MRRC (see Basic Neuroscience Program), 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 in 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 and is regulated by Sonic hedgehog. In cell culture, virus-mediated ectopic expression of Olg-1 directs multipotent cortical progenitor cells to express early markers of the oligodendrocyte lineage.
We are presently engaged in further functional analysis of Olg gene functions. Firstly, we wish to determine whether Olg gene expression is sufficient to initiate the formation of oligodendrocytes in animals, using a bigenic GAL4/UAS system to achieve conditional expression of wild type and mutated Olg genes in developing neural tube of transgenic mice. Secondly, we will determine whether Olg gene expression is necessary for oligodendrocyte development. We will generate knockouts of Olg-1 and Olg-2. The genes will be disrupted 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 Aim 3) even if there is no discernable phenotype in the Olg knockouts. Finally, we wish to determine whether Olg genes function exclusively in formation of oligodendrocytes. We will map the long-term fate of neural progenitor cells that have expressed Olg genes by mating the Olg/Cre knockout mice (Aim 2) to a "Floxed" ßgeo conditional reporter mouse strain.
