Where do glial cells come from? This is not an easy question to answer, particularly in the context of the complex vertebrate nervous system, but Margot Mayer-Pröschel and her colleagues have made significant progress towards identifying the different glial precursor cells and the lineage relationships between them. A few years ago, they isolated a tripotential glial-restricted precursor (GRP) from the vertebrate spinal cord, which, in vitro at least, can give rise to oligodendrocytes and type 1 and 2 astrocytes. Until recently, the relationship between this cell and other glial precursors was unclear, but the team now report on a new study that might provide some answers.

In vertebrates, it seems that the first step in glial cell differentiation is the generation of multipotent precursor cells, which can give rise to multiple glial lineages but not to neurons. The ability of the GRP cell to generate oligodendrocytes raises fundamental questions regarding its relationship to another oligodendrocyte ancestor, the bipotential oligodendrocyte-type-2 astrocyte progenitor cell (O2A/OPC). Do these distinct precursor cell populations independently generate oligodendrocytes, thereby providing a new example of lineage convergence (the generation of a particular differentiated cell type by more than one developmental lineage), or might there be a direct relationship between them? Gregori et al. examined the lineage relationship between the GRP cell and the O2A/OPC, asking the question: do these cells belong to separate but convergent lineages, or is the O2A/OPC derived directly from the GRP cell by a process of lineage restriction?

The authors isolated GRP cells from the embryonic day (E) 13.5 rat spinal cord, and examined their differentiation potential using clonal analysis. They showed that in the presence of platelet-derived growth factor (PDGF) and thyroid hormone (TH), these cells differentiated into cells with characteristics of O2A/OPCs; that is, they expressed O4, which is the only antigen known to distinguish O2A/OPCs from GRPs, and they could give rise to oligodendrocytes and type 2 (but not type 1) astrocytes. This indicates that GRPs can act as direct precursors of the O2A/OPCs.

What could be the role of GRPs in vivo? In this study, Gregori et al. explored their potential as oligodendrocyte precursors. Oligodendrocytes are derived predominantly from the ventral spinal cord, but at E13.5, GRPs were present throughout the dorsoventral axis. However, dorsally and ventrally derived GRPs seemed to have different properties. Although they were equally capable of generating O2A/OPCs in the presence of PDGF and TH, the ventrally derived cells were more likely to differentiate along the oligodendrocyte pathway, consistent with earlier observations on the localization of oligodendrocyte production.

So, GRPs are strong candidates for precursors of the oligodendrocyte lineage, with O2A/OPCs acting as intermediates. However, their presence in the dorsal spinal cord, combined with their ability to generate two types of astrocyte in vitro, implies a broader range of functions. Could the GRP cell possibly be the elusive universal glial precursor in the vertebrate nervous system? It is far too early to say, but this work will undoubtedly prompt further studies to show us just what GRP cells are capable of.