DIFFERENTIATION OF OLIGODENDROGLIAL PROGENITORS DERIVED FROM CORTICALMULTIPOTENT CELLS REQUIRES EXTRINSIC SIGNALS INCLUDING ACTIVATION OF GP130 LIF-BETA RECEPTORS/

We have previously isolated epidermal growth factor (EGF)-responsive m ultipotent progenitor cells from the early postnatal rodent cerebral c ortex independent of generative zones. In this study we have examined the mechanisms regulating the generation of differentiated oligodendro cytes (OLs) from these multipotent cells. Although cultures of primary cortical OL progenitor cells propagated at clonal density spontaneous ly gave rise to differentiated OLs in defined medium, cultures of mult ipotent progenitors isolated from identical regions supported the elab oration of OL progenitors but not differentiated OLs. These observatio ns indicate that the terminal maturation of OL progenitors derived fro m multipotent cells is dependent on signals present within the cellula r environment. Application of cytokines such as basic fibroblast growt h factor (bFGF), platelet-derived growth factor (PDGF), or neurotrophi n 3 (NT3) to clonal density cultures of cortical multipotent progenito rs increased the proportion of OL progenitors but failed to support th e generation of differentiated OLs. By contrast, application of factor s that activate gp130/leukemia inhibitory factor beta (LIF beta) heter odimeric receptors, such as ciliary neurotrophic factor (CNTF), activa ted signal transducers and activators of transcription-3 in these OL p rogenitor cells and promoted the generation of differentiated OLs. Clo nal analysis also demonstrated that CNTF directly targets OL progenito rs derived from the multipotent cells. These observations suggest that two distinct progenitor cell pathways contribute to the generation of differentiated OLs during postnatal cortical gliogenesis. Although ol igodendroglial maturation of classical OL progenitor cells is driven b y cell autonomous mechanisms, our findings demonstrate that the genera tion of differentiated OLs from cortical multipotent progenitor cells is dependent on environmental cues, including activation of gp130/LIF beta receptors.