The objective of this project is to define the regulatory signals that control myelination, the event where oligodendrocytes and Schwann cells extend processes that enwrap and ensheath axons. Our search for the molecular basis of transcriptional controls on myelination involves characterization of both the trans-acting regulatory factors and their cognate cis-acting enhancer/repressor elements necessary for expression of the prototype myelin gene proteolipid protein (PLP). A combination of biochemical and functional assays have revealed that most of the essential cis elements are clustered near the PLP promoter. Regulation of this region most likely involves an interplay of various tissue-specific and ubiquitous binding proteins, some of which directly interact with the cis recognition sequences and some of which bind a protein-DNA complex. We have cloned four putative transcription factors of the former class by screening brain expression libraries with recognition site DNA, and have discovered a novel member of the zinc finger class of transcription factors. The isolation of clones encoding transcriptional regulatory proteins permits a search for the growth factors and other molecules that are critical to the initiation and maintenance of myelin gene transcription. Using a demyelinating model, we have found that one such growth factor, insulin growth factor 1 (IGF-1), may be the intermediary by which astrocytes stimulate oligodendrocytes to remyelinate in vivo. PLP is the most abundant constituent of central nervous system myelin and its loss has devastating effects on myelinating cells. By defining new mutations in the PLP gene of animal and human dysmyelinating disorders, we have provided molecular evidence that these mutations act, at least in part, to interrupt oligodendrocyte differentiation.
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