Oligodendrocytes, GRPs and MNOPs.

What about earlier stages? At developmental stages earlier than E16, expression of Olig1 and Olig2 is limited to a large ventral domain of the proliferating ventricular zone that is known to generate both motoneurons and oligodendrocytes. If Olig2 expression is confined to an oligodendrocyte–motoneuron precursor, then its expression should not be seen in other lineages that can arise from the same domain, such as radial glia and S-100β-expressing astrocytes. Further, retroviral-lineage analysis should identify clones that contain oligodendrocytes and motoneurons but not other cells. However, the available data do not suggest that Olig2 expression is seen in a homogenous population (see following discussion) [7xSee all References, 14xDynamic expression of basic helix–loop–helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3. Takebayashi, H. et al. Mech. Dev. 2000; 99: 143–148Crossref | PubMed | Scopus (252)See all References, 15xNon-overlapping expression of Olig3 and Olig2 in the embryonic neural tube. Takebayashi, H. et al. Mech. Dev. 2002; 113: 169–174Crossref | PubMed | Scopus (46)See all References] (Y. Liu and M.S. Rao, unpublished). Retroviral labeling experiments performed in the chick spinal cord [16xLineage, arrangement, and death of clonally related motoneurons in chick spinal cord. Leber, S.M. et al. J. Neurosci. 1990; 10: 2451–2462PubMedSee all References, 17xLineage analysis with a recombinant retrovirus: application to chick spinal motor neurons. Leber, S.M. and Sanes, J.R. Adv. Neurol. 1991; 56: 27–36PubMedSee all References] revealed that the majority of clones that contained motoneurons also contained cells other than oligodendrocytes (in particular, astrocytes). Indeed, two cell clones consisting of only a radial glial cell and a motoneuron were also seen. This data suggests that if an oligodendrocyte–motoneuron precursor (as identified by Olig2 expression) exists, then it is at best a minor component of the heterogeneous populations present in the motoneuron-generating domain of cells. Parenthetically, it is important to note that at this stage oligodendrocyte–astrocyte clones were also identified, suggesting that alternative precursors exist.Double labeling experiments [7xSee all References][7] (Y. Liu and M.S. Rao, unpublished) confirmed the retroviral labeling results and showed Olig2 expression in a heterogeneous population of cells that included stem cells (Sox2-expressing cells), astrocytes (S-100β-expressng cells) and radial glia (RC1-expressing cells), in addition to other precursor cells [7xSee all References][7] (Y. Liu and M.S. Rao, unpublished). A similar conclusion that Olig2 expression is seen in a mixed population was reached by Takebayashi and colleagues [14xDynamic expression of basic helix–loop–helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3. Takebayashi, H. et al. Mech. Dev. 2000; 99: 143–148Crossref | PubMed | Scopus (252)See all References, 15xNon-overlapping expression of Olig3 and Olig2 in the embryonic neural tube. Takebayashi, H. et al. Mech. Dev. 2002; 113: 169–174Crossref | PubMed | Scopus (46)See all References].Initial reports indicated that Olig–CRE/Rosa–lox–β-gal mice showed β-galactosidase expression in only oligodendrocytes and motoneurons [2xCommon developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Lu, Q.R. et al. Cell. 2002; 109: 75–86Abstract | Full Text | Full Text PDF | PubMed | Scopus (588)See all References][2], which was taken as strong evidence for the existence of an oligodendrocyte–motoneuron precursor. However, we note that staining with S-100β, RC1 and other non-neuronal and oligodendrocyte markers was not undertaken. Indeed, in recent experiments we have re-examined Olig1–CRE/Rosa–lox–β-gal mice and have shown that Olig1-expressing precursors can generate radial glia and astrocytes in addition to motoneurons and oligodendrocytes (Y. Liu and M.S. Rao, unpublished).We would also point out that, by contrast, evidence for a bipotential oligodendrocyte–astrocyte precursor (i.e. a GRP) is provided by retroviral lineage analysis in vivo [11xMultipotential and lineage restricted precursors coexist in the mammalian perinatal subventricular zone. Levison, S.W. and Goldman, J.E. J. Neurosci. Res. 1997; 48: 83–94Crossref | PubMedSee all References, 12xCycling cells in the adult rat neocortex preferentially generate oligodendroglia. Levison, S.W. et al. J. Neurosci. Res. 1999; 57: 435–446Crossref | PubMed | Scopus (139)See all References, 18xBoth oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain. Levison, S.W. and Goldman, J.E. Neuron. 1993; 10: 201–212Abstract | Full Text PDF | PubMed | Scopus (507)See all References], clonal analysis in vitro [19xGlial-restricted precursors are derived from multipotent neuroepithelial stem cells. Rao, M.S. and Mayer-Proschel, M. Dev. Biol. 1997; 188: 48–63Crossref | PubMed | Scopus (204)See all References, 20xA tripotential glial precursor cell is present in the developing spinal cord. Rao, M.S. et al. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3996–4001Crossref | PubMed | Scopus (225)See all References], transplant experiments [10xSee all References, 11xMultipotential and lineage restricted precursors coexist in the mammalian perinatal subventricular zone. Levison, S.W. and Goldman, J.E. J. Neurosci. Res. 1997; 48: 83–94Crossref | PubMedSee all References] and, more recently, by analysis of FGFR3-null mice that show an oligodendrocyte–astrocyte phenotype [21xFibroblast growth factor receptor 3 signaling regulates the onset of oligodendrocyte terminal differentiation. Oh, L.Y. et al. J. Neurosci. 2003; 23: 883–894PubMedSee all References][21], making it difficult to discount the existence of a GRP based on the existing MNOP data.The current data do not warrant concluding that an MNOP precursor exists; rather, they illustrate the necessity of additional experiments. Indeed, these additional experiments might well also force a re-evaluation of the GRP hypothesis. We welcome feedback from readers on data that we might have overlooked.