Oligodendrocyte Specification

Oligodendrocyte Specification 209

Oligodendrocyte Specification
W D Richardson, University College London,London, UK
ã 2009 Published by Elsevier Ltd.

Specification of OligodendrocytePrecursor Cells in the EmbryonicNeural Tube

All the neurons and glial cells of the central nervoussystem (CNS) are derived from the neuroepithelialprogenitor cells that form the walls of the embryonicneural tube. The neuroepithelial cell layer (ventricularzone (VZ)) of the spinal cord and brain stem can besubdividedalong thedorsal–ventralaxis into11distinctmicrodomains, defined by expression of different com-binations of transcription factors (Figure 1). Theseprogenitor domains generate different types of neuronsfollowed by glial cells (oligodendrocytes or astrocytes).Fully differentiated glia are not formed directly fromthe neuroepithelium but via intermediate glial precur-sors. During or after neuronogenesis, the neuroepithe-lial progenitors give rise to so-called radial glial cells,which express characteristic gene products such asthe glutamate transporter GLAST and the radialcell antigen RC2. Radial glia subsequently generatededicated astrocyte or oligodendrocyte precursors. Ina given domain of the VZ, radial glia produce eithermainlyastrocytesormainlyoligodendrocytes.Forexam-ple, thepMNdomainof theventral spinal cord (Figure1)generates motor neurons followed by oligodendrocyteprecursors (OPCs) but few astrocytes. Overall, appro-ximately 80% of spinal cord oligodendrocytes arederived from ventrally derivedOPCs, mainly pMN, andthe remaining 20% from OPCs that originate in dorsaldomains dP3–5 (Figure 1).

Visualizing Oligodendrocytes and TheirPrecursors In Situ

From the earliest stages of their development, migra-tory OPCs can be visualized by immunohistochemis-try or in situ hybridization against a characteristicset of markers, including the platelet-derived growthfactor receptor (a subunit) (PDGFRA), the proteogly-can NG2, the transcription factor SOX10, and, inchicken only, surface antigens recognized by mono-clonal antibody O4. In rodents, O4 antigen does notappear until a later, premyelinating stage (called pro-oligodendrocytes) when the precursors have stoppedmigrating and are beginning to differentiate intooligodendrocytes. In both birds and rodents, actively

myelinating oligodendrocytes can be easily recognizedby the expression of proteins (or correspondingmRNAs) that are abundant structural components ofmyelin, such as myelin basic protein and myelin pro-teolipid protein.

Using these and othermolecular markers, it has beenshown that OPCs are first generated in the pMN pro-genitor domain of the ventral spinal cord at 12.5 dayspostfertilization (E12.5) in mice, E14 in rats, and E6or E7 in chick. In human spinal cord, OPCs appearon or before 45days postfertilization. The followingdiscussion, unless otherwise stated, refers to mouse.After the OPCs first appear at the ventricular surface,they proliferate and migrate throughout the cord,becoming evenly distributed through the gray matterand developing white matter before birth. Starting atapproximately E18 (birth is approximately E19 inmice), oligodendrocyte differentiation starts in theventral white matter and continues for approximately6weeks, peaking at approximately postnatal days10–14. In human spinal cord,myelination of corticosp-inal tracts continues into the teenage years.

Spatial Control of OPC Generation bySignals from the Ventral andDorsal Midline

In the ventral spinal cord, specification of both motorneurons and OPCs depends on signaling moleculesthat are secreted from the notochord and floor plateat the ventral midline, notably the secreted proteinSonic hedgehog (SHH). If chicken embryos are trea-ted in ovo with cyclopamine, an inhibitor of SHHsignaling, then the appearance of OPCs in the ventralspinal cord is blocked. Conversely, supplying anectopic source of SHH (e.g., by implanting SHH-expressing cells or fragments of notochord adjacentto the spinal cord) induces extra OPCs in misplacedpositions. Members of the bone morphogenetic pro-tein (BMP) family of signaling molecules are alsoinvolved in limiting the spatial extent of OPC genera-tion in the ventral cord. BMPs (notably BMP2 andBMP4) are expressed in the dorsal spinal cord andexert long-range influences along the dorsal–ventralaxis. This has been demonstrated by surgically remov-ing the BMP-expressing domain in ovo or by trans-planting cells that express the competitive BMPinhibitor Noggin next to the chick spinal cord. Boththese manipulations caused the OPC-producing pMNdomain to expand dorsally. The extra OPCs weregenerated at the expense of astrocytes, which are nor-mally produced in the p2 progenitor domain, immedi-ately dorsal to pMN. Therefore, it seems that the

Spinal cord progenitor domains,transcription factors and cell fates

RP

FP

INs, astrocytes,OPCs

INs, astrocytes

MNs, OPCs

dP1

dP2

dP3

dP4

dP5dP6

p0

p1

p2

pMN

p3

msx3

pax7dbx1

nkx6.2

nkx2.2

nkx6.1

olig2

Figure 1 Diagram of progenitor domains in the VZ of the embry-

onic (�E11) mouse spinal cord. Domains are known as p3, pMN,

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

transcription factors, some of which are mentioned in the text.

Dotted lines with small arrows indicate that the expression domain

expands or shrinks after it is first established. On the right are

shown the cell fates of progenitors in the indicated domains (the

origins of astrocytes are still tentative). FP, floor plate; INs, inter-

neurons; MNs, motor neurons; OPCs, oligodendrocyte precursor

cells; RP, roof plate.

210 Oligodendrocyte Specification

spatial extent of OPC and astrocyte production in theventral cord is limited by mutually antagonisticactions of SHH and BMPs.The majority (approximately 80%) of OPCs in the

spinal cord are generated in the ventral VZ. Theremainder are generated in other progenitor domains,including dorsal domains dP3–5. The dorsally derivedOPCs appear later in development than the pMN-derived OPCs (approximately E15 vs. E12.5) andthey migrate less widely than their ventrally derivedcounterparts. It seems unlikely that these dorsal pro-genitor domains are under the influence of SHH fromthe floor plate, suggesting that there might be a SHH-independent route to OPC specification. Indeed,OPCs can arise in cultures derived from SHH nullspinal cord or in the presence of cyclopamine, if fibro-blast growth factor-2 (FGF-2) is also present in theculture medium. OPC generation in the dorsal spinalcord might therefore depend on FGF signaling, pos-sibly combined with a decline in BMP expression inthe dorsal cord during late embryogenesis. Theremight even be a biochemical overlap between SHHand FGF signaling because it has been shown thatboth pathways depend on MAP kinase activity.It is not known whether or not ventrally and dor-

sally derived OPCs in the spinal cord are function-ally specialized. However, there is evidence that

ventrally and dorsally derived OPCs in the forebraincan substitute for one another, implying that they arefunctionally equivalent.

OPC Generation in the Forebrain

The adult forebrain, including the cerebral cortex,develops from an embryonic structure called the tel-encephalon. Like the spinal cord, this starts as a simpleneuroepithelial tube, although it becomes progres-sively more convoluted during development. There isno notochord underlying the telencephalon and nofloor plate; however, the ventral neuroepithelial cellsexpress SHH and its receptors, Patched (PTC) andSmoothened (SMO). At approximately E13.5, somecells in the ventral neuroepithelium (medial gangli-onic eminence (MGE)) start to express OPC markerssuch as PDGFRA and SOX10 and migrate away fromtheir origin through the ventral telencephalon. Gener-ation of these early OPCs depends on SHH becausethey do not appear in embryos that lack SHH expres-sion in the ventral telencephalon (Nkx2.1 null mice).Later, other parts of the VZ generate OPCs in a tem-poral wave of production from ventral to dorsal.OPCs from the MGE and lateral ganglionic eminence(LGE) initially populate the developing forebrainincluding the cerebral cortex before birth, to be joinedafter birth by OPCs that originate within the cortex.The latter OPCs remain in the cortex and do notmigrate ventrally.

The question of whether all these OPCs and theoligodendrocytes that they give rise to are functionallyspecialized, or equivalent, was addressed by kill-ing specific subpopulations of OPCs at source. Thiswas achieved by targeting diphtheria toxin A-chainexpression to subpopulations of OPCs that originatein different domains of the telencephalic neuroepithe-lium (MGE, LGE, and cortex) by combinatorial use ofan oligodendrocyte lineage-specific gene promoter(Sox10) and one of several promoters that are activein different parts of the VZ (Nkx2.1, Gsh2, orEmx1).These experiments showed that when OPCs originat-ing within the cortical VZ (normally approximately50% of all OPCs in the cortex) were ablated, theremaining ventrally derived populations expanded tomake up the loss and the animals survived and lived anormal life span. Even when all telencephalic OPCsfrom MGE, LGE, and cortex were ablated simulta-neously, they were replaced by OPCs that migratedforward from the diencephalon. A normal OPC celldensitywas restored –with a significant but ultimatelyharmless delay – indicating that OPCs from differentparts of the embryonic neuroepithelium are not intrin-sically different from one another despite the verydifferent signaling environments in which they arise.


Of course, there might be subtle differences thatwould not be detected without detailed behavioralanalysis of the ablated mice, but this remains to beinvestigated.

Role of Transcription Factors in OPCDevelopment: The OLIG Genes

A major step forward in understanding the molecularcontrol of oligodendrocyte lineage developmentresulted from the discovery of transcription factorsthat orchestrate OPC specification and differentia-tion. Prime among these are the oligodendrocytelineage (OLIG) transcription factors, OLIG1 andOLIG2. These are members of the large family ofbasic helix–loop–helix factors that also includes thepro-neural proteins NGN1/2 andMASH1 and the celllineage regulators MYOD and NEUROD. In thedeveloping spinal cord, SHH induces expression ofOLIG2 in pMN, prior to and during motor neuron(MN) production. OLIG2 is downregulated rapidlyin postmitotic MNs but remains on in OPCs as theyproliferate and migrate away through the paren-chyma. OLIG2 is required for both MN and OPCspecification because both cell types are lost inOlig2 null spinal cords. Pockets of OPCs persist inthe brains of Olig2 null mice, but no OPCs are foundanywhere in the CNS of Olig1/2 compound nulls.Therefore, OLIG1 might partly compensate for lossof OLIG2 in the brain. There is no effect on OPCgeneration in either the brain or the spinal cord ofOlig1 null mice, although there can be severe myeli-nation defects later. OLIG1 therefore seems to bemainly involved in the later stages of oligodendrocytedifferentiation and myelination.

Figure 2 (a) Immunolabeling of ventral progenitor domains p3 and p

factors NKX2.2 and OLIG2, respectively. Motor neurons are still bei

(p3, green), OLIG2 (pMN, blue), and PDGFRA (newly forming OPCs,

formed mainly within the OLIG2-expressing pMN domain in mouse, ou

the ventricular surface, the OPCs migrate away rapidly in all direction

Note that different laboratories have reported dif-ferent experiences withOlig1 knockoutmice, depend-ing on whether or not the PGK-Neo cassette usedto inactivate the locus was removed prior to estab-lishing mouse lines. When the PGK-Neo cassette wasleft in place, there was no obvious dysmyelinatingphenotype during development, possibly because ofcis-acting effects of the PGK-Neo transcription uniton the nearby Olig2 gene. However, even in thelatter mice there was a striking effect on remyelinationof adult mice that were subjected to gliotoxin-inducedexperimental demyelination; such demyelinatedlesions are rapidly repaired in wild-type mice butremyelination was blocked in the Olig1 knockouts.

The underlying mechanism by which OLIG2 gov-erns the sequential production of MNs and OPCs(‘neuron–glial switch’) is not known. Presumably,OLIG2 switches binding partners (transcriptionalcofactors) during the transition fromMN to OPC pro-duction. During the period ofMN production, OLIG2and the homeodomain transcription factor NKX2.2are mutually repressive so that the OLIG2 andNKX2.2 expression domains (pMN and p3, respec-tively) are sharply demarcated (Figure 2). Later, afterMN production has ceased, the cross-repression seemsto relax because NKX2.2 expression creeps dorsallyinto pMN and an overlap region develops. Initially, itwas thought that OPCs might be generated specificallywithin this overlap region under the cooperative activ-ities of OLIG2 and NKX2.2. In chick, it does appearthat PDGFRAþ OPCs are formed exclusively withinthe overlap region, but inmiceOPCs arise in all parts ofthe OLIG2-expressing pMN domain, not just theregion of overlap with NKX2.2 (Figure 2). Moreover,OPC specification is not affected inNkx2.2 null mice,

MN in the mouse spinal cord with antibodies against transcription

ng generated at E11. (b) Three-color immunolabeling of NKX2.2

red) in the mouse ventral spinal cord at E13. The first OPCs are

tside the NKX2.2-expressing p3 domain. After they are formed at

s to populate the spinal cord.


although the later stages of oligodendrocyte differenti-ation and myelination are delayed. A similar delay inmyelination is observed in mice that lack the highmobility group transcription factor SOX10, which isknown to interactwithOLIG1 andOLIG2.OLIG2hasalso been shown to interact physically with NKX2.2.Therefore, a picture is emerging in which OLIG1/2,NKX2.2, and SOX10 cooperate in controlling myelingene expression and axon ensheathment. OLIG2 andother members of the SOX family (including SOX8and SOX9) are required earlier for OPC and/or MNspecification, but so far there is no compelling explana-tion for the neuron–glial switch.Notch–Delta signaling is clearly involved in the

MN/OPC fate choice as in many other binary deci-sions during development. It has been shown that, inzebra fish, abrogation of Notch signaling results inexcess production of MNs at the expense of OPCs.Conversely, constitutive activation of Notch signalingresults in excess OPCs at the expense of MNs. Awell-established general function of Notch–Delta signalingis to maintain precursor cells in an immature stateand to inhibit premature cell cycle exit and differenti-ation, thus preserving part of the precursor pool forgeneration of later-born cell types. Since MNs areformed before OPCs, the gain- and loss-of-functionexperiments in zebra fish spinal cord can be inter-preted in those terms – implying that Notch signalingmight play a permissive rather than an instructive rolein the MN/OPC fate choice.

Control of OPC Proliferation

After they are specified in the embryonic VZ, OPCsproliferate and migrate away from their sites of origin,distributing widely and uniformly throughout the CNSbefore associating with axons and differentiating intomyelin-forming oligodendrocytes (Figure 3). Several

Figure 3 OPCs, visualized by in situ hybridization forPdgframRNA,

at approximately E12.5, and then they proliferate in response to PDGF-

becoming widely distributed by approximately E15. They first start to

tracts soon before birth (E19 in mice).

mitogenic polypeptides have been shown to influenceOPC proliferation in culture and/or in vivo, includingPDGF, FGF, and cytokines. These probably act in con-cert with one another, possibly in different combina-tions in different regions of the CNS and/or at differentstages of OPC development.

OPCs express receptors for PDGF (PDGFRA sub-type), and many neurons and astrocytes synthesizePDGF-A. PDGF-A null mice have reduced OPC num-bers (approximately 10% normal numbers in the spi-nal cord and approximately 50% in the cerebralcortex) and correspondingly reduced amounts ofmye-lin. Therefore, homodimeric PDGF-AA is an essentialmitogen for OPCs in vivo. PDGF-AA is also stronglymitogenic for OPCs in mixed neural cell cultures,such asmixed glial cell cultures derived from perinatalrat optic nerve. However, PDGF-AA is not verymitogenic for pure, immunoselected populations ofOPCs cultured on their own in the absence of othercell types. There are other essential mitogens or mito-genic cofactors released into the extracellular mediumof mixed cell cultures that are required to cooperatewith PDGF-AA. One of these is the CXC cytokineGRO-alpha. Astrocytes are a major source of GRO-alpha in optic nerve cultures and probably alsoin vivo. Cell adhesion molecules, notably integrinfamily members, also synergize with PDGF and possi-bly other polypeptide mitogens to drive OPC prolifer-ation at limiting mitogen concentrations.

FGF-2 also enhances the mitogenic effect of PDGF-AA for OPC glial cell cultures. OPCs cultured withboth PDGF-AA and FGF-2 can proliferate seeminglyindefinitely without differentiating, whereas PDGF-AA in the absence of FGF allows limited OPC prolif-eration followed by oligodendrocyte differentation.FGF-2 on its own in the absence of PDGF is mitogenicfor a late stage of OPC development, when OPCsstop migrating and express the O4 antigen prior to

in the developingmouse spinal cord. The first OPCs appear in pMN

AA and other mitogenic cofactors andmigrate throughout the cord,

differentiate into oligodendrocytes in the ventral and dorsal axon


terminal oligodendrocyte differentiation – so-called‘pro-oligodendrocytes.’ Studies on the role of FGFin vivo are complicated by the large number of poten-tial ligands (>20 FGF family members) and the factthat OPCs express different FGF receptor subtypes(FGFR1–3) at different stages of their development.Nevertheless, retrovirus-mediated inhibition of FGF-2activity in vivo has shown that FGF-2, acting throughFGFR1, negatively regulates OPC terminal differentia-tion into oligodendrocytes during normal developmentand after experimental demyelination in adult mice.Other signaling systems that have been implicated in

the control ofOPC proliferation include neurotrophin-3, neuregulin-1/glial growth factor (NRG1/GGF), andinsulin-like growth factor-1. There is also a growingawareness of the importance of ion channels and neu-rotransmitters inOPC proliferation and differentiationcontrol.

Control of OPC Differentiation

After OPCs have disseminated throughout the CNSand into the future gray and white matter, somethingtriggers them to differentiate into oligodendrocytes.One key signal seems to be the thyroid hormonetriiodothyronine (T3), a constituent of the definedculture medium commonly used for primary nervecells. When T3 is omitted from the culture medium,OPCs divide for an extended period in response toPDGF-AA, well beyond their normal limit in thepresence of T3. It appears that T3 is required forwithdrawal from the cell cycle prior to terminal dif-ferentiation. This effect of T3 can be mimicked byglucocorticoids or retinoic acid.There is an established literature on the role of

thyroid hormone (TH) in brain development andmyelination. The start of myelination is delayed inhypothyroid rats and accelerated in hyperthyroid ratsor rats that receive postnatal injections of T3. More-over, TH normally only becomes available in the ratwhen the thyroid gland becomes active after birth,which is approximately the time when myelin firststarts to appear. Oligodendrocytes and OPCs possessreceptors for T3, so it is likely that T3 acts directly onOPCs to control their differentiation in vivo.Notch signaling is also implicated in the control of

oligodendrocyte differentiation. OPCs expressNotch-1,and adding the Notch ligand Jagged to optic nerve cellcultures inhibits OPC differentiation into oligodendro-cytes in vitro. Jagged is expressed on optic nerve axonsin vivo, suggesting that differentiation of OPCs in theoptic nervemight be triggered in part bydownregulationof Jagged in the retinal ganglion cells that project theiraxons through the nerve. In support of this general idea,

conditional deletion of Notch-1 in OPCs in transgenicmice leads to premature expression of oligodendrocytedifferentiation markers such as the myelin-associatedglycoprotein.

Control of Myelination byNeuregulin-1/Glial Growth Factor

Not all axons are myelinated: Axons must reach acertain minimum size (diameter) threshold beforemyelination is triggered. Below this threshold theaxon remains naked. This is true in both the CNSand the peripheral nervous system (PNS). In addition,there is a direct relationship between the diameter ofa myelinated axon and the thickness of the myelinsheath that develops around that axon (i.e., larger diam-eter axons have more myelin wraps). The myelin-modulating signal resides on the axonal surface and isinterpreted by the myelinating glia (oligodendrocytesor Schwann cells) which adjust their synthesis ofmyelin membrane accordingly.

Neuregulins are a family of signaling proteinsencoded in three loci,Nrg1–3, each of which generatesalternatively spliced products that can be eithersecreted or membrane bound. They bind to receptorsof the ErbB family (ErbB1–4), which includes the epi-dermal growth factor receptor ErbB1. NRG1 type III,also known as GGF, is now known to be the mainaxon-bound regulator of myelination in the PNS, act-ing through ErbB receptors on Schwann cells. Theexpectation that one or more NRG isoforms mightalso regulate myelinogenesis in the CNS is supportedby the finding that expressing a dominant negativeErbB transgene in oligodendrocytes results in thinnermyelin sheaths and associated physiological deficits,including reduced conduction velocity and, unexpect-edly, increased dopaminergic activity of neurons. Theprecise NRG isoform responsible is not known. Theseinitial results are exciting because of the implied linksbetween myelin deficiency, neuronal activity, and,potentially, psychiatric illness.

OPCs in the Adult CNS

Myelination continues for at least 6weeks postna-tally in mice and rats, peaking 2 or 3weeks afterbirth. However, cells with the antigenic phenotypeand morphology of OPCs persist in large numbers inthe adult CNS (approximately 4% of all cells). Liketheir perinatal counterparts, they continue to expressboth PDGFRA and the NG2 proteoglycan and retainthe capacity to generate oligodendrocytes in cul-ture or following experimentally induced demyelina-tion. However, because there has been no compellingreason to think that significant numbers of new

Figure 4 Individual oligodendrocyte lineage cells labeled in situ (in 300-mm live sections of postnatal mouse corpus callosum) by

microinjection of fluorescent Alexa dye. The myelinating oligodendrocyte (b) was formed between 6 and 8weeks after birth from a

PDGFRA-expressing adult OPC/NG2 cell (a). The long rod-like processes in b are myelin sheaths (‘internodes’) around nerve axons.

Micrographs courtesy of M Rizzi.


oligodendrocytes are needed during normal healthylife, why large numbers of OPCs should survive in theadult has been puzzling.It has been recognized that OPCs in the adult make

contact with nodes of Ranvier (the gaps between adja-cent myelin sheaths on an axon), they receive synapticinput from neurons, and they can even fire spontane-ous action potentials. This has led to the notion thatOPCs participate in the normal physiology of the adultCNS and that their primary role is not necessarily asglial precursors. They have been called ‘a fourth glialcell type’ (after astrocytes, oligodendrocytes, andmicroglia), ‘synantocytes,’ ‘polydendrocytes,’ or, morecommonly, ‘NG2 cells.’ The physiological role of thesecells is under intense scrutiny.We should not reject the idea that NG2 cells might

be needed to generate new or replacement oligo-dendrocytes throughout life. Cre-lox fate mappingin adult mice (using tamoxifen-inducible Pdgfra-CreERT2) shows that they continue to divide andgenerate significant numbers of new myelinatingoligodendrocytes in the corpus callosum of adult ani-mals (Figure 4). Whether this ongoing oligodendro-genesis occurs to replace cells that die through naturalturnover or to add extra oligodendrocytes to theexisting pool is not known. It is now accepted thatnew neurons are generated in some parts of the adultbrain throughout life; for example, new olfactoryinterneurons are continuously generated from stemcells that reside in the adult subventricular zonesof the forebrain. It is conceivable that some adult-born neurons might need to be myelinated, and thiscould be one important function of the adult NG2cells. Alternatively, or in addition, the axonal dia-meters of some previously unmyelinated neurons

might increase during life, taking them over thethreshold for de novo myelination.

Finally, NG2 cells might have more general cell fatepotential. It is known that OPCs in perinatal opticnerve cell cultures can give rise to neurons, astrocytes,and oligodendrocytes if cultured in an appropriatemanner. It is therefore possible, though not yet demon-strated, that OPCs in the adult CNS might be able togenerate new neurons or astrocytes aswell as oligoden-drocytes. If so, adult OPCs/NG2 cells would qualify asa type of adult neural stem cells.

See also: Drosophila Apterous Neurons: from Stem Cell to

Unique Neuron; Motor Neuron Specification in

Vertebrates; Myelin: Molecular Architecture of CNS and

PNS Myelin Sheath; Neurotransmitter and Hormone

Receptors on Oligodendrocytes and Schwann Cells;

Oligodendrocyte Morphology; Oligodendrocyte and

Schwann Cell Identification Methods.

Further Reading

Barres BA and RaffMC (1994) Control of oligodendrocyte number

in the developing rat optic nerve. Neuron 12: 935–942.

Coman I, Barbin G, Charles P, Zalc B, and Lubetzki C (2005)Axonal signals in central nervous system myelination,

demyelination and remyelination. Journal of NeurologicalScience 233: 93–97.

Karadottir R and Attwell D (2007) Neurotransmitter receptors inthe life and death of oligodendrocytes. Neuroscience 145:

1426–1438.

Miller RH (2002) Regulation of oligodendrocyte development inthe vertebrate CNS. Progress in Neurobiology 67: 451–467.

Nishiyama A (2007) Polydendrocytes: NG2 cells with many roles

in development and repair of the CNS. Neuroscientist 13:

62–76.


Polito A and Reynolds R (2005) NG2-expressing cells as oligoden-

drocyte progenitors in the normal and demyelinated adult cen-

tral nervous system. Journal of Anatomy 207: 707–716.

Raff M (2006) The mystery of intracellular developmental pro-grammes and timers. Biochemical Society Transactions 34:

663–670.

Richardson WD (2001) Oligodendrocyte development. In: JessenKR, and Richardson WD (eds.) Glial Cell Development, 2ndedn., pp. 21–54. Oxford: Oxford University Press.

Richardson WD, Kessaris N, and Pringle NP (2006) Oligodendro-

cyte wars. Nature Reviews Neuroscience 7: 11–18.Rowitch DH (2004) Glial cell specification in the vertebrate neural

tube. Nature Reviews Neuroscience 5: 409–419.WegnerM and Stolt CC (2005) From stem cells to neurons and glia:

A Soxist’s view of neural development. Trends in Neurosciences28: 583–588.

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Oligodendrocyte Specification