This group has pioneered the characterization of glial precursor cells from neonatal brain cultures. In the present proposed plan of study, we will investigate the molecular mechanisms affecting the developmental events of cells in the oligodendrocyte (OL) lineage. The OL lineage offers an excellent system to address the effect of environmental signalling agents, such as growth factors and hormones, on the phenotypic progression of these cells. Utilizing probes for growth factor and transcription factors, we will conduct a comparative developmental time course analysis of OL cell lineage phenotypes. During neonatal development, OLs can be characterized by the sequential appearance of cell-specific markers such as glycerol phosphate dehydrogenase (GPDH), myelin basic protein (MBP), and proteolipid protein (PLP). this differential gene expression is modulated by epigenetic factors that participate in normal brain development. Transcriptional activation of these genes is considered to be dependent upon the expression of a set of rapidly induced early response genes (ERGs). In this study we propose to characterize the molecular mechanisms responsible for cell-type specific, stage-specific and hormonally-mediated transcriptional activation of GPDH, an important marker of the differentiating OL lineage cell. In addition, we will examine the molecular events leading to the glucocorticoid-mediated post- transcriptional regulation of MBP and PLP gene expression. We will use the myelin-deficient (md) rat model to study the differentiation of the OL cell lineage. An alteration of a single nucleotide in the PLP gene has been identified in these animals and absence of CNS myelin has been reported. In md animals, we observed an impairment in expression of MBP, PLP, and GPDH mRNA at the cytosolic level even though the rate of transcription of MBP and GPDH in md is normal. Therefore, we propose to examine the post- transcriptional regulation of myelin gene expressions in md rats and to investigate the role of PLP regulation of OL marker gene expression. This proposal impacts on problems of nervous system development since alterations of gene expression due to genetic and environmental factors are the major causes of mental retardation and developmental disabilities.
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