Within the central nervous system (CNS), the greatest progress in identifying the specific cell populations involved in development has been achieved in the spinal cord. In the rat spinal cord, E10.5 cells have been shown to represent a homogenous population of multipotent neuroepithelial stem cells (NEPs) capable of generating cells of both the neuronal and glial lineage. Differentiated cell types arise from these NEP cells by way of lineage restricted intermediate precursor populations capable of extended proliferation and the generation of neurons or glia. The cells comprising the earliest intermediate precursor population restricted to oligodendrocyte and astrocyte formation, called glial restricted precursor cells (GRPs), can be isolated from the embryonic spinal cord as early as E12. Their ability to generate two antigenically distinct populations of astrocytes and oligodendrocytes has been established both in vitro and in vivo (for review see [1, 2]). GRP cells are identified with the A2B5 antibody and do not express the Polysialylated form of Neural Cell Adhesion Molecule (PSA-NCAM). Freshly isolated GRP cells depend on basic fibroblast growth factor (bFGF) for survival and proliferation but, unlike oligodendrocyte progenitor cells (OPCs ), are not defined by the expression of platelet-derived growth factor receptor-alpha (PDGFR-alpha) or Olig2 . The OPC has been shown in vivo to arise at a later time point than the GRP, and the generation of oligodendrocytes from a GRP population has been demonstrated in vitro to occur through an OPC intermediate stage . Importantly, in both the GRP and OPC populations, the term restricted is used to underscore the greatly diminished, if not non-existent, capacity for neuronal generation when compared to multipotent NEP cells. To date, GRP cells isolated from the spinal cord have failed to generate neurons in numerous paradigms including transplantation into the embryonic spinal cord [5–7]. It has, however, been reported that glial precursor cells isolated from the postnatal optic nerve can be induced to express neuron-like features if cultured for at least one month in serum containing medium , although the significance of this "neuronal potential" remains unclear.
Additional characteristics distinguishing GRP cells from OPCs are the ability of GRP cells to generate two types of astrocytes (that have been designated type-1 and type-2 ) in vitro and to generate both oligodendrocytes and astrocytes in vivo. Both type-1 and type-2 astrocytes are GFAP+, but only type-1 astrocytes co-label with the A2B5 antibody. Type-1 astrocytes are thought to arise from GRP cells through intermediate astrocyte progenitor cells (APC) , while type-2 astrocytes may require prior generation of OPCs as an intermediate step . Unlike OPCs, GRP cells readily generate astrocytes following transplantation into the adult CNS , while primary OPCs thus far only generate oligodendrocytes in such transplantations .
The identification of GRP cells in the spinal cord gave rise to a generalized model of gliogenesis consistent with the majority of experimental data available. This model of gliogenesis involves the progression from a multipotential NEP cell to a lineage restricted multipotent precursor cell population (e.g. GRPs) that in turn give rise to more restricted glial precursor cell types (e.g. OPCs and possibly APCs) and the eventual mature glial cells of the CNS (e.g. oligodendrocytes and astrocytes)[2, 12–14]. While the generation of each cell type in the lineage and the resultant appropriate cellular fate of astrocyte or oligodendrocyte are governed by environmental cues, not all potential cell fates that are observed in vitro may be witnessed in vivo, requiring a careful consideration when interpreting in vitro and in vivo experiments.
In contrast to the spinal cord, the identification of intermediate cellular components of glial cell generation in the telencephalon is largely incomplete. With the OPC the major focus thus far in studies on glial cell generation in the telencephalon, the extent of similarity between intermediate glial precursor cells of the spinal cord and telencephalon is largely unknown. It has been ascertained through genetic and clonal in vitro experiments that a subset of cells from ventral regions of the telencephalon differentiate into PDGFR-alpha+ and/or Olig2+ oligodendrocyte progenitors, migrate away from their ventral origin, and give rise to mature oligodendrocytes throughout the brain [15–20]. It is further assumed that these cells need to express Olig1/2 to be fated towards oligodendrocytes as compound disruption of Olig1 and Olig2 results in a complete loss of oligodendrocytes [21–27]. While these experiments led to the view that the major source for telencephalic oligodendrocytes are ventrally generated OPCs, recent evidence indicates there might be a dorsal origin for a subset, if not majority, of telencephalic oligodendrocytes .
Several populations of PDGFR-alpha+ OPCs in the telencephalon have been identified, each with distinctive spatial and temporal origins [24, 26, 27], but whether the OPC represents the only glial restricted cell in the telencephalon remains unknown. This deficit in our understanding of the glial progenitor populations present in the developing telencephalon also raises the question as to which cells are involved in the generation of astrocytes, a critical cell component of the telencephalon. In addition, while it is well established that cortical NEPs generate neurons, astrocytes, and oligodendrocytes, it is unclear whether or not mature, cortical glial cells are derived from lineage restricted precursor cells or are the product of migrating stem cells in vivo. Although precursor cell populations responsible for glial cell formation in the telencephalon have been described [20, 24, 26, 28], to date no embryonic telencephalic cell has been identified and isolated that possesses the ability to generate both oligodendrocytes and astrocytes in the absence of neuron generation in vitro or in vivo.
With a growing interest in and an increased appreciation for the therapeutic potential of spinal cord derived GRPs  and the role of precursor populations in disease , the aims of this study were to investigate the presence of progenitor populations capable of generating oligodendrocytes and astrocytes but unable to generate neurons, and to determine whether such a progenitor population is derived dorsally and/or ventrally. We began our analysis by isolating cell populations from the dorsal telencephalon based on the antigenic phenotype of restricted precursor cells previously identified in the spinal cord. These telencephalic cells were characterized in mass culture and at the clonal level and were found to generate all macroglial subtypes but were unable to generate neurons. We further determined the dorsal telencephalon is capable of generating this glial restricted population de novo by separating the dorsal telencephalon at a time point where the cell populations present are exclusively of a dorsal origin. In line with the potential dorsal origin of this glial restricted cell population, we identified a ventral glial restricted cell population in parallel. We confirmed the ability of the dorsal cell population to differentiate into myelin producing oligodendrocytes upon transplantation in a myelin deficient background, as well as GFAP+ astrocytes when transplanted into the perinatal forebrain. To our knowledge, these findings represent the first identification of progenitor cells in the embryonic telencephalon that are able to generate both oligodendrocytes and astrocytes but are unable to generate neuronal progeny. Our study also provide for the first time a defined cell population that is generated de novo in the dorsal aspect of the telencephalon and could be the source for both dorsally derived oligodendrocytes and astrocytes. Taken together, our findings provide a general model of gliogenesis by which glial cells originate in a timely and organized manner in the developing telencephalon. This identification and characterization of a telencephalic glial restricted progenitor population is an important step in understanding early telencephalic oligodendrocyte and astrocyte generation and provides a foundation for further investigation into normal and abnormal telencephalic glial cell development.