Patricia A. Wight
Ph.D, University of California, Riverside
Office: (501) 686-5366
Lab: (501) 686-5367
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.
Hamdan H., Kockara N.T., Jolly L.A., Haun S., and Wight P.A. (2015) Control of human PLP1 expression through transcriptional regulatory elements and alternatively spliced exons in intron 1. ASN Neuro 7(1) pii: 1759091415569910
Pereira G.B., Meng F., Kockara N.T., Yang B., and Wight P.A. (2013) Targeted deletion of the antisilencer/enhancer (ASE) element from intron 1 of the myelin proteolipid protein gene (Plp1) in mouse reveals that the element is dispensable for Plp1 expression in brain during development and remyelination J. Neurochem. 124:454-465.
Zolova O.E. and Wight P.A. (2011) YY1 Negatively Regulates Mouse Myelin Proteolipid Protein (Plp1) Gene Expression in Oligodendroglial Cells. ASN Neuro 3(4):223-232.
Pereira G.B., Dobretsova A., Hamdan H., and Wight P.A. (2011) Expression of myelin genes: comparative analysis of Oli-neu and N20.1 oligodendroglial cell lines. J. Neurosci. Res. 89:1070-1078
Li S., Greuel B.T., Meng F., Pereira G.B., Pitts A., Dobretsova A., and Wight P.A. (2009) Leydig cells express the myelin proteolipid protein gene and incorporate a new alternatively spliced exon. Gene 436:30-36
Dobretsova A., Johnson J.W., Jones R.C., Edmondson R.D., and Wight P.A. (2008) Proteomic analysis of nuclear factors binding to an intronic enhancer in the myelin proteolipid protein gene. J. Neurochem. 105:1979-1995.
Wight P.A., Duchala C.S., Gudz T.I., Shick H.E., and Macklin W.B. (2007) Expression of a myelin proteolipid protein (Plp)-lacZ transgene is reduced in both the CNS and PNS of Plpjp mice. Neurochem. Res. 32:343-351.
Meng F., Zolova O., Kokorina N.A., Dobretsova A., and Wight P.A. (2005) Characterization of an intronic enhancer that regulates myelin proteolipid protein (Plp) gene expression in oligodendrocytes. J. Neurosci. Res. 82:346-356.
Dobretsova A., Kokorina N.A., and Wight P.A. (2004) Potentiation of myelin proteolipid protein (Plp) gene expression is mediated through AP-1-like binding sites. J. Neurochem. 90:1500-1510.
Wight P. A. and Dobretsova A. (2004) Where, when and how much: regulation of myelin proteolipid protein gene expression. Cell. Mol. Life Sci. 61:810-821.
Li S., Moore C.L., Dobretsova A., and Wight P.A. (2002). Myelin proteolipid protein (Plp) intron 1 DNA is required to temporally regulate Plp gene expression in the brain. J. Neurochem. 83:193-201.
Li S., Dobretsova A., Kokorina N.A., and Wight P.A. (2002) Repression of myelin proteolipid protein gene expression is mediated through both general and cell type-specific negative regulatory elements in non-expressing cells. J. Neurochem. 82:159-171.