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 that 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 in oligodendrocytes, with peak expression occurring during the active 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) or spastic paraplegia type 2 (SPG2). Transgenic mice carrying a null mutation or extra copies of the gene demonstrate 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 abuts/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 1) identifying the transcription factors/architectural proteins that mediate enhancer function in PLP1 intron 1; 2) test whether critical mutations in the enhancer could be the cause of PMD/SPG2 in patients having a normal PLP1 coding sequence and the standard gene dosage; 3) elucidate the spatiotemporal expression and function of PLP1 splice variants that incorporate a ‘human-specific’ exon from what is classically defined as intron 1. We are also using our PLP1-lacZ transgenic mice as a tool to screen for small molecules that stimulate remyelination, as possible therapies for demyelinating diseases such as multiple sclerosis.
A separate project in the laboratory seeks to identify the genetic cause of mesenchymal phenotype that spontaneously arose in one of our mouse colonies.