The neuroepithelium gives rise to all the major classes of cells in the mature vertebrate CNS including neurons, astrocytes and oligodendrocytes. In most cases, the regulation of commitment of neuroepithelial cells to a specific fate and the control of precursor cell migration and differentiation is unknown. We have demonstrated that oligodendrocyte precursors in the developing rat spinal cord are initially located only in ventral regions of the spinal cord and during subsequent development migrate dorsally where they differentiate into myelin forming cells. More recently we identified a specific location in the ventral ventricular zone of the chick spinal cord in which precursors become committed to oligodendrocytes, and we described a ventral to dorsal gradient of oligodendrocyte differentiation. These observations led us to propose that the notochord, a ventrally located transient embryonic structure regulates the development of spinal cord oligodendrocytes. To determine if signals from the notochord influence the pattern of oligodendrocyte development, and whether the notochord is essential for the subsequent development of spinal cord oligodendrocytes, we will perform notochord transplantation and ablation studies in chick and Xenopus embryos. In order to myelinate CNS regions devoid of intrinsic oligodendrocyte precursors and to ameliorate pathologically demyelinated adult CNS regions, oligodendrocyte precursors must migrate considerable distances. We demonstrated that rat optic nerve oligodendrocytes were derived from progenitor cells that migrated from the brain during development, while the myelination of the complete spinal cord is dependent on the ventral to dorsal migration of oligodendrocyte precursors. Based on these studies we propose that there are-distinct pathways utilized for migration of oligodendrocyte precursors in the CNS. We have recently developed an immunolabeling paradigm which for the first time allows us to examine directly the characteristics of actively migrating oligodendrocyte precursors in vivo. Using a combination of light and electron microscopic assays, we will determine the cellular substrates of oligodendrocyte precursor migration in the intact CNS. Further, to identify the molecular mechanisms mediating oligodendrocyte precursor migration, in vivo antibody perturbation studies will be compared with the analysis of oligodendrocyte precursor migration over defined molecular substrates in vitro. These studies will provide new and important information on the regulation of oligodendrocyte development in the vertebrate CNS. Such information is essential for designing successful approaches to induce remyelination following injury or demyelinating diseases such as multiple sclerosis.