The mechanisms that dictate the final program of gene expression in a fully differentiated cell can be revealed by starting at either end of the regulatory cascade. To examine the series of controls operating on cells of the oligodendrocyte lineage, we have cloned a number of putative transcription factors that recognize one of the final targets of regulation in myelinating glial cells, proteolipid protein (PLP). One such factor named MyTI (myelin transcription factor I) is a novel member of the zinc finger superfamily. Several observations suggest that MyTI may be instrumental in early stages of oligodendrocyte development and myelin production. MyTI message is highly expressed in oligodendrocyte progenitors and absent in mature oligodendrocytes. MyTI protein appears as speckles within the nucleus of progenitors, suggestive of an association of MyTI with spatially segregated functional domains. MyTI has two clusters of DNA-binding domains, one of which binds to a consensus site represented several times in the PLP promoter and also found in other myelin genes. Experiments are underway to explore the physical interactions of MyTI with DNA through bending assays, the in vivo function of MyTI through knockout mice, and the nature of the subnuclear domains in which MyTI is segregated by two approaches, an immunocytochemical colocalization of MyTI with other nuclear proteins found in discrete nuclear domains and an interaction cloning scheme using the yeast two-hybrid system. The MyTI gene resides on human chromosome 2; this mapping data may be useful in evaluating patients with inherited white matter disorders that resemble Pelizaeus-Merzbacher disease but do not carry mutations at the PLP locus, as these patients are candidates for mutations in MyTI or one of the other transcription factors that control myelination. An additional member of the MyTI family, which is also expressed in the developing nervous system, has been isolated and mapped to human chromosome 20. MyTI may represent an emerging class of regulatory proteins with a combination of features that predicts a role in coordinating the expression of a set of genes. Characteristic features shared by such proteins would include a structure of multiple DNA-binding domains which are each stabilized by a divalent cation, initial expression that markedly precedes the target gene, and localization within discrete macromolecular compartments of the nucleus. Identifying genes like MyTI that may be responsible for transforming a precursor cell into a myelinating oligodendrocyte is a prerequisite for designing strategies to stimulate remyelination in inherited or acquired white matter disorder.
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