Myelination is a critical developmental process that, when altered, results in severe neurological dysfunction. The overall goal of our research is directed toward obtaining a better understanding of the role myelin proteins play in the myelination of the central nervous system (CNS). Additionally, the function of myelin proteins in the differentiation of oligodendrocytes, the myelinating cell of the CNS, will be examined. The gene encoding the myelin basic protein (MBP) will be analyzed in the dysmyelinating murine mutant myelin deficient (mld). The mld MBP gene is organized as a tandem duplication with the upstream gene containing an inversion of its 3' region. The DNA sequence surrounding the breakpoints of the inversion/duplication will be determined in an effort to identify regions associated with the recombinational events responsible for the gene rearrangement. The mld MBP gene is expressed at decreased levels and on an abnormal developmental schedule. Several in vitro and in vivo approaches will be taken to determine the basis of this altered MBP expression. The dysmyelinating murine mutation jimpy results in proteolipid (PLP) and DM-20 protein deficiencies, CNS hypomyelination, and oligodendrocyte death. Transgenic jimpy animals will be generated that express either only PLP or DM-20 in an attempt to determine the effect these proteins have on myelination and oligodendrocyte survival in these animals. Efforts will also be made to inactivate the myelin protein genes in transgenic mice. Animals will be generated that contain a vast molar excess of the cis regions involved in regulating myelin protein gene expression. By functionally depleting oligodendrocytes of the myelin protein genes trans-activator proteins, inhibition of the transcriptional activity of these genes should occur.
