A network of genes is recruited in developing oligodendrocytes to coordinate the production of myelin, a deficiency of which can drastically impair neuronal function in the central nervous system. Mechanisms operative in regulating myelin gene expression can be revealed by defining the set of transcription factors and signaling pathways that are selectively and temporally activated in developing oligodendrocytes. To examine the changing pattern of transcription factors and other genes selectively expressed by developing oligodendrocytes, we established a reliable microarray system combined with purification of oligodendrocytes by flow cytometry at different stages of differentiation. Such an approach has enabled the isolation and profiling of a novel, non-myelinating population of oligodendrocytes. The function and regulation of several genes expressed by this population of non-myelinating oligodendrocytes is being further examined in transgenic models to identify the molecular basis for the switch from a non-myelinating to a myelinating phenotype. Genetic profiling also revealed a family of semaphorin ligands and their cognate neuropilin receptors that influence the migration of oligodendrocyte progenitors (Cohen et al., 2003). Another signalling pathway involving the tyrosine protein phosphatase epsilon was implicated in axon-glial interactions in the optic nerve (Muja et al., in press). For the Myt1 myelin transcription factor, which modulates oligodendrocyte differentiation and proliferation (Nielsen et al., 2004), we defined an interaction with a transcriptional co-repressor, Sin3, that may locally modify chromatin structure to regulate myelin gene transcription. Combining transcriptomics with in vivo demyelinating paradigms, we have begun to evaluate the transcriptional response to myelin loss and the signaling that ensues between oligodendrocytes and their neuronal targets. These studies form the basis for devising strategies to promote remyelination in diseases such as multiple sclerosis, Pelizaeus-Merzbacher disease and spinal cord injury by stimulating endogenous oligodendrocyte progenitors to proliferate, migrate and myelinate.
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