Morphogenesis does not always precede the cell-type expression of genes characteristic of a terminally differentiated cell. In the nervous system, two examples of this phenomenon are the myelin-specific gene encoding proteolipid protein (PLP) of oligodendrocytes and the gene encoding the neurotransmitter biosynthetic enzyme GAD (glutamic acid decarboxylase) in neurons, both of which are actively expressed long before the appearance of the appropriately differentiated cell. How these genes are activated very early in development and what possible functions the encoded proteins assume in these precursor cells are the focus of this project. The basic approach, which is ongoing in both cases, entails constructing and evaluating transgenic mice in which the target gene or putative transcription factor(s) have been knocked out. A long-term objective of our group has been to define the regulatory signals that control myelination, the event where oligodendrocytes extend processes that enwrap and ensheath axons. Our search for the molecular basis of transcriptional controls on myelination has identified both putative trans-acting regulatory factors and their cognate cis-acting enhancer/repressor elements necessary for expression of the prototype myelin gene proteolipid protein. One of the transcription factors that we cloned based on its ability to recognize the PLP promoter is a novel member of the zinc finger superfamily of DNA-binding proteins. The structure and expression of this protein, which appears to be restricted to cells that are the progenitors of oligodendrocytes, suggests that it may play an architectural role in organizing the PLP locus for transcriptional activation. The isolation of 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. We have found one such growth factor, IGF-I that may be an intermediary by which astrocytes stimulate oligodendrocytes to myelinate in vivo. This system provides a handle for identifying second messengers that may relay information to the transcriptional machinery of cells in the oligodendrocyte lineage, and therefore will enable a look at the molecular events that underlie the signalling of oligodendrocytes by astrocytes.
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