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Oligodendrocyte Specification 209 Oligodendrocyte Specification 209 Oligodendrocyte Specification W D Richardson, University College London, myelinating oligodendrocytes can be easily recognized London, UK by the expression of proteins (or corresponding ã 2009 Published by Elsevier Ltd. mRNAs) that are abundant structural components of myelin, such as myelin basic protein and myelin pro- teolipid protein. Using these and other molecular markers, it has been Specification of Oligodendrocyte shown that OPCs are first generated in the pMN pro- Precursor Cells in the Embryonic genitor domain of the ventral spinal cord at 12.5 days Neural Tube postfertilization (E12.5) in mice, E14 in rats, and E6 or E7 in chick. In human spinal cord, OPCs appear All the neurons and glial cells of the central nervous on or before 45 days postfertilization. The following system (CNS) are derived from the neuroepithelial discussion, unless otherwise stated, refers to mouse. progenitor cells that form the walls of the embryonic After the OPCs first appear at the ventricular surface, neural tube. The neuroepithelial cell layer (ventricular they proliferate and migrate throughout the cord, zone (VZ)) of the spinal cord and brain stem can be becoming evenly distributed through the gray matter subdivided along the dorsal–ventralaxisinto 11 distinct and developing white matter before birth. Starting at microdomains, defined by expression of different com- approximately E18 (birth is approximately E19 in binations of transcription factors (Figure 1). These mice), oligodendrocyte differentiation starts in the progenitor domains generate different types of neurons ventral white matter and continues for approximately followed by glial cells (oligodendrocytes or astrocytes). 6 weeks, peaking at approximately postnatal days Fully differentiated glia are not formed directly from 10–14. In human spinal cord, myelination of corticosp- the neuroepithelium but via intermediate glial precur- inal tracts continues into the teenage years. sors. During or after neuronogenesis, the neuroepithe- lial progenitors give rise to so-called radial glial cells, which express characteristic gene products such as Spatial Control of OPC Generation by the glutamate transporter GLAST and the radial Signals from the Ventral and cell antigen RC2. Radial glia subsequently generate Dorsal Midline dedicated astrocyte or oligodendrocyte precursors. In a given domain of the VZ, radial glia produce either In the ventral spinal cord, specification of both motor mainly astrocytes or mainly oligodendrocytes. For exam- neurons and OPCs depends on signaling molecules ple, the pMN domain of the ventral spinal cord (Figure 1) that are secreted from the notochord and floor plate generates motor neurons followed by oligodendrocyte at the ventral midline, notably the secreted protein precursors (OPCs) but few astrocytes. Overall, appro- Sonic hedgehog (SHH). If chicken embryos are trea- ximately 80% of spinal cord oligodendrocytes are ted in ovo with cyclopamine, an inhibitor of SHH derived from ventrally derived OPCs, mainly pMN, and signaling, then the appearance of OPCs in the ventral the remaining 20% from OPCs that originate in dorsal spinal cord is blocked. Conversely, supplying an domains dP3–5 (Figure 1). ectopic source of SHH (e.g., by implanting SHH- expressing cells or fragments of notochord adjacent to the spinal cord) induces extra OPCs in misplaced Visualizing Oligodendrocytes and Their positions. Members of the bone morphogenetic pro- Precursors In Situ tein (BMP) family of signaling molecules are also involved in limiting the spatial extent of OPC genera- From the earliest stages of their development, migra- tion in the ventral cord. BMPs (notably BMP2 and tory OPCs can be visualized by immunohistochemis- BMP4) are expressed in the dorsal spinal cord and try or in situ hybridization against a characteristic exert long-range influences along the dorsal–ventral set of markers, including the platelet-derived growth axis. This has been demonstrated by surgically remov- factor receptor (a subunit) (PDGFRA), the proteogly- ing the BMP-expressing domain in ovo or by trans- can NG2, the transcription factor SOX10, and, in planting cells that express the competitive BMP chicken only, surface antigens recognized by mono- inhibitor Noggin next to the chick spinal cord. Both clonal antibody O4. In rodents, O4 antigen does not these manipulations caused the OPC-producing pMN appear until a later, premyelinating stage (called pro- domain to expand dorsally. The extra OPCs were oligodendrocytes) when the precursors have stopped generated at the expense of astrocytes, which are nor- migrating and are beginning to differentiate into mally produced in the p2 progenitor domain, immedi- oligodendrocytes. In both birds and rodents, actively ately dorsal to pMN. Therefore, it seems that the 210 Oligodendrocyte Specification Spinal cord progenitor domains, ventrally and dorsally derived OPCs in the forebrain transcription factors and cell fates can substitute for one another, implying that they are RP functionally equivalent. dP1 dP2 OPC Generation in the Forebrain dP3 INs, astrocytes, The adult forebrain, including the cerebral cortex, dP4 msx3 OPCs develops from an embryonic structure called the tel- dP5 encephalon. Like the spinal cord, this starts as a simple pax7 dP6 dbx1 neuroepithelial tube, although it becomes progres- p0 INs, astrocytes sively more convoluted during development. There is nkx6.2 p1 no notochord underlying the telencephalon and no nkx6.1 p2 floor plate; however, the ventral neuroepithelial cells olig2 pMN MNs, OPCs express SHH and its receptors, Patched (PTC) and nkx2.2 p3 Smoothened (SMO). At approximately E13.5, some cells in the ventral neuroepithelium (medial gangli- FP onic eminence (MGE)) start to express OPC markers Figure 1 Diagram of progenitor domains in the VZ of the embry- such as PDGFRA and SOX10 and migrate away from onic ( E11) mouse spinal cord. Domains are known as p3, pMN, their origin through the ventral telencephalon. Gener- etc. in the ventral half of the cord and dP6, dP5, etc. in the dorsal half. To the left of the diagram are shown the expression limits of ation of these early OPCs depends on SHH because transcription factors, some of which are mentioned in the text. they do not appear in embryos that lack SHH expres- Dotted lines with small arrows indicate that the expression domain sion in the ventral telencephalon (Nkx2.1 null mice). expands or shrinks after it is first established. On the right are Later, other parts of the VZ generate OPCs in a tem- shown the cell fates of progenitors in the indicated domains (the poral wave of production from ventral to dorsal. origins of astrocytes are still tentative). FP, floor plate; INs, inter- neurons; MNs, motor neurons; OPCs, oligodendrocyte precursor OPCs from the MGE and lateral ganglionic eminence cells; RP, roof plate. (LGE) initially populate the developing forebrain including the cerebral cortex before birth, to be joined after birth by OPCs that originate within the cortex. spatial extent of OPC and astrocyte production in the The latter OPCs remain in the cortex and do not ventral cord is limited by mutually antagonistic migrate ventrally. actions of SHH and BMPs. The question of whether all these OPCs and the The majority (approximately 80%) of OPCs in the oligodendrocytes that they give rise to are functionally spinal cord are generated in the ventral VZ. The specialized, or equivalent, was addressed by kill- remainder are generated in other progenitor domains, ing specific subpopulations of OPCs at source. This including dorsal domains dP3–5. The dorsally derived was achieved by targeting diphtheria toxin A-chain OPCs appear later in development than the pMN- expression to subpopulations of OPCs that originate derived OPCs (approximately E15 vs. E12.5) and in different domains of the telencephalic neuroepithe- they migrate less widely than their ventrally derived lium (MGE, LGE, and cortex) by combinatorial use of counterparts. It seems unlikely that these dorsal pro- an oligodendrocyte lineage-specific gene promoter genitor domains are under the influence of SHH from (Sox10) and one of several promoters that are active the floor plate, suggesting that there might be a SHH- in different parts of the VZ (Nkx2.1, Gsh2,orEmx1). independent route to OPC specification. Indeed, These experiments showed that when OPCs originat- OPCs can arise in cultures derived from SHH null ing within the cortical VZ (normally approximately spinal cord or in the presence of cyclopamine, if fibro- 50% of all OPCs in the cortex) were ablated, the blast growth factor-2 (FGF-2) is also present in the remaining ventrally derived populations expanded to culture medium. OPC generation in the dorsal spinal make up the loss and the animals survived and lived a cord might therefore depend on FGF signaling, pos- normal life span. Even when all telencephalic OPCs sibly combined with a decline in BMP expression in from MGE, LGE, and cortex were ablated simulta- the dorsal cord during late embryogenesis. There neously, they were replaced by OPCs that migrated might even be a biochemical overlap between SHH forward from the diencephalon. A normal OPC cell and FGF signaling because it has been shown that density was restored – with a significant but ultimately both pathways depend on MAP kinase activity. harmless delay – indicating that OPCs from different It is not known whether or not ventrally and dor- parts of the embryonic neuroepithelium are not intrin- sally
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