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Oligodendrocytes are the cells responsible for the formation of myelin in the central nervous system. Recent studies demonstrated that cells of the oligodendrocyte lineage initially arise in distinct regions of the ventricular zone during early development. These cells or their progeny migrate to developing white matter tracts where they undergo the majority of their proliferation and subsequently differentiate into myelinating cells. Oligodendrocyte-precursor cell proliferation is regulated by a number of distinct growth factors that act at distinct stages in the lineage and the final number of oligodendrocytes in any region of the CNS is regulated by local influences. A density-dependent feedback inhibition of proliferation reduces the responsiveness of the cells to their growth factors and the final matching of oligodendrocyte and axon number is accomplished through the local regulation of cell death. In this review, we discuss the major factors that regulate three distinct stages in the development of the oligodendrocyte lineage: The initial induction of oligodendrocyte progenitors, the regulation of expansion and dispersion of the committed precursor cell population, and the final regulation of oligodendrocyte precursor number through the local inhibition of oligodendrocyte precursor proliferation and cell death.

Oligodendrocytes are responsible for myelin formation in spinal cord white matter. In the mature spinal cord, the majority of white matter is localized peripherally. During early development, however, the first oligodendrocyte precursors arise in the ventral ventricular zone of the developing cord. Thus, prior to myelination, both migration and proliferation of oligodendrocyte precursors must occur. When and where these events occur is currently unclear. In the chick spinal cord, oligodendrocyte precursors express antigens recognized by the monoclonal antibody O4. Here we show that all chick spinal cord oligodendrocytes are derived from O4+ cells and all O4+ cells appear to give rise to oligodendrocytes. Analysis of the number and distribution of oligodendrocyte precursors in chick spinal cord at different stages of development suggests that relatively few cells migrate from the ventricular source which then proliferate extensively in white matter. This migration is guided by general dispersive cues. Clonal analysis of oligodendrocyte development in cultures derived from different regions of the rodent spinal cord indicated that the cells that initially populate dorsal and peripheral spinal cord retained similar clonal properties to those in ventral spinal cord, suggesting the migrating cells were immature, highly proliferative precursors. Consistent with these results, BrdU incorporation studies indicate that glial proliferation is extensive and persistent in postnatal rat spinal cord white matter. Together, these studies suggest that spinal cord white matter is initially populated by very immature precursors that then undergo extensive local proliferation prior to myelination.

During spinal cord development, oligodendrocytes originate in a discrete region of the ventral ventricular zone. What regulates this initial localization of oligodendrocyte precursors is unclear. Using a combination of notochord transplantations in vivo and co-culture experiments, we demonstrate that the origin of chick spinal cord oligodendrocytes is dependent on local influences from the notochord. In stage 10-12 dorsal chick spinal cord, Mab O4+ oligodendrocyte precursors were induced both in vivo by isochronic transplantation of an additional notochord adjacent to the dorsal neural tube and in vitro by co-culture of notochord and dorsal neural tube. Heterochronic transplantations demonstrated that the notochord was capable of inducing O4+ cells in adjacent neural tube until stage 12 and that the competence of the dorsal neural tube to respond to this inductive signal declined after stage 10. During normal development the ventral neural tube is competent to develop oligodendrocytes independent of the notochord by stage 10. The induction of oligodendrocytes by the notochord may either reflect a direct interaction or be mediated through other ventrally located cells such as the floor plate. In the majority of experimental animals the appearance of ectopic oligodendrocyte precursors was correlated with local floor plate formation.

During development of the vertebrate central nervous system, many types of neural precursors originate in the ventricular zone of the central nervous system (CNS) and migrate through the neuropil to their final destination. In embryonic rat spinal cord, the ventral ventricular zone gives rise to neurons, astrocytes, and oligodendrocyte precursors. We have used a spinal cord stripe preparation to examine the migration of neural precursors from different regions of the spinal cord ventricular zone in vitro. Astrocyte and oligodendrocyte precursors, neurons, and neurites all emigrated from stripes of embryonic day 14 (E14) rat ventral spinal cord while only neurites emigrated in significant numbers from stripes of E14 dorsal spinal cord. The first wave of migrating cells from E14 ventral spinal cord stripes comprised a population of A2B5+ astrocyte precursors that exhibited a semicircular or ellipsoid morphology and showed an unusual form of lamellipodia-based motility. These cells were highly motile, migrating at rates of approximately 20 microns/h. The cortical region of the rapidly translocating astrocyte precursors contained high levels of actin microfilaments oriented in a circumferential band, but few microtubules. In their morphology, cytoskeletal organization, and rapid translocation, this subpopulation of vertebrate CNS glial precursors more closely resemble epidermal keratocytes than other neural cells. The rapid translocation exhibited by A2B5+ astrocyte precursors may reflect a role in CNS wound healing and be responsible for the rapid spread of some forms of CNS glial tumors.