Developmental Control Of Gene Expression In The Brain

Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

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. Toward this end, we identified semaphorin ligands and their cognate neuropilin receptors that influence the migration of oligodendrocyte progenitors. We also discovered an oligodendrocyte transmembrane protein (OTMP) that is selectively expressed by non-myelinating oligodendrocytes. The function and regulation of this gene is being further examined in a transgenic approach to identify the molecular basis for the switch from a non-myelinating to a myelinating phenotype. We published the first molecular examination of nuclear structure in oligodendrocytes, in which we documented the spatial organization of myelin transcription factors, splicing factors and myelin genes. For one of the myelin transcription factors, Myt1, we defined an interaction with a transcriptional co-repressor, Sin3, that may locally modify chromatin structure to regulate myelin gene transcription. To examine the changing pattern of transcription factors expressed by developing oligodendrocytes, we set up a reliable microarray system. Using this genetic profiling approach in conjunction 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. Finally, we evaluated marmoset bone marrow as a potential source for transplantable oligodendrocytes in a rat demyelinating model, and concluded that the transdifferentiation potential of these cells for the oligodendrocyte lineage was minimal. These studies form the basis for devising strategies to promote remyelination in diseases such as multiple sclerosis, Pelizaeus-Merzbacher disease and spinal cord injury, either by directly supplying normal progenitors or by stimulating endogenous oligodendrocyte progenitors to proliferate, migrate and differentiate.