An alternate pathway for postnatal oligodendrogliogenesis outside of generative zones

Abstract

Although lineage specification during development is thought to be restricted to generative zones, regional differences within the evolving cerebral cortex may require a mechanism for the elaboration of individual neural lineages in response to local environmental signals. To examine this hypothesis, we have isolated an enriched population of very early neural progenitor cells that express the polysialylated form of neural cell adhesion molecule (PSA-NCAM) from postnatal day two cerebrum independent of generative zones. A subpopulation of progenitor cells exhibited robust proliferation in response to epidermal growth factor and subsequently gave rise to clonally-derived neurons, astrocytes and oligodendrocytes. Next, we examined whether the differentiation of post-mitotic oligodendrocytes from multipotent progenitor cells is regulated by intrinsic cellular mechanisms or by specific cytokines that are expressed within the cerebrum during postnatal development. We have utilized clonal density cultures of cortical PSA-NCAM-positive multipotent progenitors and have demonstrated that these cells give rise to oligodendroglial (OL) progenitors but not to post-mitotic oligodendrocytes. Application of ciliary neurotrophic factor (CNTF) to clonal density cultures supported the generation of post-mitotic oligodendrocytes and induced phosphorylation and nuclear translocation of STAT-3 in conical multipotent progenitor cells. These experimental observations suggest that the generation of post-mitotic oligodendrocytes from conical multipotent progenitor cells is dependent on local environmental cues and selective activation of gp130/LIF{dollar}\beta{dollar}R heterodimeric signaling pathways. We next thought to determine whether glia generated from cortical multipotent progenitor cells differ from glia derived from committed glioblasts. While committed PSA-NCAM-positive oligodendroglioblasts isolated directly from the cortex responded only to platelet-derived growth factor (PDGF), oligodendroblasts derived from cortical multipotent progenitors exhibited responsiveness to PDGF or to neurotrophin-3 (NT-3). These experimental observations suggest the presence of a distinct pathway for the migration of multipotent progenitor cells and their retention within the postnatal cerebrum. This pathway may provide a mechanism by which local cues refine regional cellular interactions and compensate for random morphogenetic errors. Moreover, therapeutic interventions aimed at differentiation of endogenous cerebral pools of multipotent progenitors may provide a novel strategy for amelioration of the sequelae of environmental and genetic insults to the postnatal cerebrum.