The focus of research in my laboratory is centered on CNS development, particularly with regard to the formation and maintenance of myelin. Myelin is the tightly compacted multilamellar sheath, which surrounds axons and promotes saltatory conduction of nerve impulses. The myelin proteolipid protein gene (PLP1) encodes the most abundant protein found in mature myelin from the CNS. Expression of the gene is regulated spatiotemporally, with maximal expression occurring in oligodendrocytes during the myelination period of CNS development. PLP1 expression is tightly controlled; misregulation of the gene in humans can result in the X-linked dysmyelinating disorder Pelizaeus-Merzbacher disease (PMD), and in transgenic mice carrying a null mutation or extra copies of the gene can result in a variety of conditions from late onset demyelination and axonopathy to severe early onset dysmyelination. With the use of transgenic and transfection paradigms, we have been able to show that the first intron of the PLP1 contains an enhancer region that is required for expression in oligodendrocytes as well as in other cell types that express PLP1. This region also overlaps a couple of recently discovered, alternatively spliced exons that are primarily restricted to the human species. Current efforts in the laboratory are focused on: identifying the transcription factors/architectural proteins that mediate enhancer function in PLP1 intron 1; test whether critical mutations in the enhancer could be the cause of PMD in patients with unaltered PLP1 coding sequence and gene dosage; understand the and spatiotemporal expression and function of intron 1-dervied splice isoforms in man. We are also using our PLP1-lacZ transgenic mice as a tool to screen for small molecules that stimulate myelination as a possible therapeutic for demyelinating diseases such as multiple sclerosis.