Oligodendrocyte lineage and the motor neuron connection.

One of the more surprising recent discoveries in glial biology has been that oligodendrocytes (OLs) originate from very restricted regions of the embryonic neural tube. This was surprising because myelinating OLs are widespread in the mature central nervous system, so there was no reason to suspect that their precursors should be restricted. What we now know about early OL development suggests that they might have as much (or more) in common with ventral neurons-specifically motor neurons (MNs)-as with other types of glia. This has implications for the way we think about glial development, function, and evolution. In this article we review the evidence for a shared MN-OL lineage and debate whether this is the only lineage that generates OLs. We decide in favour of a single embryonic lineage with regional variations along the anterior-posterior neuraxis.

Pax6 influences the time and site of origin of glial precursors in the ventral neural tube.

Neuroepithelial precursors in the ventral ventricular zone (VZ) of the spinal cord generate motor neurons (MNs) and interneurons, and then a subset of precursors starts to produce oligodendrocyte progenitors (OLPs). We show that OLPs originate in the ventral-most part of the Pax6-positive VZ, which at earlier times generates somatic (Isl2/Lim3-positive) MNs. In Small eye (Pax6-deficient) mice, the origin of OLPs is shifted dorsally and both OLPs and Isl2/Lim3 MNs are delayed. We suggest that somatic MNs and OLPs are generated sequentially from a common set of MN-OL precursors whose position in the VZ is influenced by Pax6. Neuron-glia fate switching might be a preprogrammed property of these precursors or a response to feedback from newly generated neurons. OLs developed normally in explants of Isl1(-/-) spinal cords, which lack MNs, arguing against feedback control and suggesting that the neuron-glia switch is an intrinsic developmental program in a specific subset of neural precursors.

Dorsal spinal cord neuroepithelium generates astrocytes but not oligodendrocytes.

There is evidence that oligodendrocytes in the spinal cord are derived from a restricted part of the ventricular zone near the floor plate. An alternative view is that oligodendrocytes are generated from all parts of the ventricular zone. We reinvestigated glial origins by constructing chick-quail chimeras in which dorsal or ventral segments of the embryonic chick neural tube were replaced with equivalent segments of quail neural tube. Ventral grafts gave rise to both oligodendrocytes and astrocytes. In contrast, dorsal grafts produced astrocytes but not oligodendrocytes. In mixed cultures of ventral and dorsal cells, only ventral cells generated oligodendrocytes, whereas both ventral and dorsal cells generated astrocytes. Therefore, oligodendrocytes are derived specifically from ventral neuroepithelium, and astrocytes from both dorsal and ventral.

Normal temporal and spatial distribution of oligodendrocyte progenitors in the myelin-deficient (md) rat.

A point mutation in exon 3 of the proteolipid protein (PLP) gene of the myelin-deficient (md) rat leads to a failure of oligodendrocyte maturation and early death of oligodendrocytes, resulting in dysmyelination. It has been suggested that an alternative-splice isoform of PLP, known as DM-20, might be expressed in oligodendrocyte progenitors in the embryonic central nervous system (CNS), raising the possibility that early development of the oligodendrocyte lineage might also be affected in the md rat. To test this suggestion, we visualized oligodendrocyte progenitors in the embryonic md rat spinal cord and brain by in situ hybridization with a probe to the platelet-derived growth factor alpha receptor (PDGFR). We could detect no abnormalities in the time of first appearance of oligodendrocyte precursors, nor in their subsequent proliferation and dispersal throughout the CNS. These data strongly suggest that the PLP mutation in the md rat primarily or exclusively affects the later stages of oligodendrocyte lineage.

Origins of spinal cord oligodendrocytes: possible developmental and evolutionary relationships with motor neurons.

Spinal cord oligodendrocytes develop from migratory glial progenitor cells that are generated by a small subset of neuroepithelial cells in the ventral part of the neural tube. Specification of these neuroepithelial oligodendrocyte precursors, in common with other ventral cells such as motor neurons, depends on morphogenetic signals from the notochord and/or floor plate. The ventrally derived signals can be mimicked in vitro by purified Sonic hedgehog (Shh) protein. Oligodendrocytes and motor neurons are induced over the same range of concentrations of Shh, consistent with the idea that Shh might specify a common precursor of motor neurons and oligodendrocytes. A lineage relationship between motor neurons and oligodendrocytes has previously been suggested by clonal analysis in the embryonic chick spinal cord. We propose a lineage diagram that connects oligodendrocytes and motor neurons and that takes into account the fact that motor neurons and oligodendrocyte precursors are generated at different times during development. Oligodendrocytes might originally have evolved to ensheath motor axons and facilitate a rapid escape response. If so, oligodendrocyte ontogeny and phylogeny might share a common basis.

Determination of neuroepithelial cell fate: induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog.

Near the floor plate of the embryonic neural tube there is a group of neuroepithelial precursor cells that are specialized for production of the oligodendrocyte lineage. We performed experiments to test whether specification of these neuroepithelial oligodendrocyte precursors, like other ventral neural cell types, depends on signals from the notochord and/or floor plate. We analyzed heterozygous Danforth's short tail (Sd/+) mutant mice, which lack a notochord and floor plate in caudal regions of the neural tube, and found that oligodendrocyte precursors did not appear at the ventricular surface where there was no floor plate. Moreover, oligodendrocytes did not develop in explant cultures of Sd/+ spinal cord in the absence of a floor plate. When a second notochord was grafted into an ectopic position dorsolateral to the endogenous notochord of a chicken embryo, an additional floor plate was induced along with an ectopic focus of oligodendrocyte precursors at the ventricular surface. Oligodendrocytes developed in explants of intermediate neural tube only when they were cocultured with fragments of notochord or in the presence of purified Sonic hedgehog (Shh) protein. Thus, signals from the notochord/floor plate, possibly involving Shh, are necessary and sufficient to induce the development of ventrally derived oligodendroglia. These signals appear to act by specifying the future fate(s) of neuroepithelial cells at the ventricular surface rather than by influencing the proliferation or differentiation of prespecified progenitor cells in the parenchyma of the cord.

Embryonic expression of myelin genes: evidence for a focal source of oligodendrocyte precursors in the ventricular zone of the neural tube.

2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP) is an abundant protein of myelinating oligodendrocytes. We report that one of the alternatively spliced CNP mRNAs is also expressed in cultured oligodendrocyte progenitor cells. In situ hybridization revealed a thin longitudinal column of CNP-positive cells in the ventral ventricular zone of the embryonic day 14 rat spinal cord, coincident in time and space with cells that express the platelet-derived growth factor alpha receptor, another putative marker of the oligodendrocyte lineage. These data support the hypothesis that the oligodendrocyte lineage originates at a discrete location in the ventral ventricular zone of the embryonic day 14 rat spinal cord. We further report that transcripts encoding the myelin proteolipid protein (PLP/DM-20) are expressed in an unidentified population of neural progenitors in the ventricular zone abutting the floor plate. Our results support the idea that the ventricular zone is a mosaic of specialized progenitor cells.

A singularity of PDGF alpha-receptor expression in the dorsoventral axis of the neural tube may define the origin of the oligodendrocyte lineage.

During rat embryogenesis, PDGF alpha receptor (PDGF-alpha R) mRNA is expressed in the ventral half of the spinal cord in two longitudinal columns, one each side of the central canal. Initially, these columns are only two cells wide but the cells subsequently appear to proliferate and disseminate throughout the spinal cord. Our previous studies of PDGF-alpha R expression in the developing CNS suggested that PDGF-alpha R may be a useful marker of the oligodendrocyte lineage in situ. The data presented here complement those studies and lead us to propose that the earliest oligodendrocyte precursors in the spinal cord originate in a very restricted region of the ventricular zone during a brief window of time around embryonic day 14 (E14). In the embryonic brain, migrating PDGF-alpha R+ cells appear to originate in a localized germinal zone in the ventral diencephalon (beneath the foramen of Monro). Our data demonstrate that gene expression and cell fate can be regulated with exquisite spatial resolution along the dorsoventral axis of the mammalian neural tube.

PDGF receptors in the rat CNS: during late neurogenesis, PDGF alpha-receptor expression appears to be restricted to glial cells of the oligodendrocyte lineage.

Using in situ hybridization, we have visualized cells in the rat central nervous system (CNS) that contain mRNA encoding the platelet-derived growth factor alpha receptor (PDGF-alpha R). After embryonic day 16 (E16), PDGF-alpha R mRNA appears to be expressed by a subset of glial cells, but not by neurons. The temporal and spatial distribution of PDGF-alpha R+ cells, together with 125I-PDGF binding studies on subsets of glial cells in vitro, suggests that PDGF-alpha R may be expressed predominantly, or exclusively, by cells of the oligodendrocyte-type-2 astrocyte (O-2A) lineage. This conclusion is supported by the fact that the numbers of PDGF-alpha R+ cells in developing and adult optic nerves correlate well with independent estimates of the number of O-2A progenitor cells in the nerve at equivalent ages. Small numbers of PDGF-alpha R+ cells are present in the brain at E16, at which time they are found outside the subventricular germinal zones, suggesting that these cells do not express PDGF-alpha R until after, or shortly before they start to migrate away from the subventricular layer towards their final destinations. Reduced numbers of PDGF-alpha R+ cells persist in the adult CNS. PDGF-alpha R is also expressed strongly in the meningeal membranes and choroid plexus, and in the inner limiting membrane of the retina.