the process of myelination is an exquisite and dynamic example of cell  cell interaction , which consists of the concentric wrapping of multiple layers of membrane around an axon . this process requires a series of highly orchestrated events that balance both intrinsic and extrinsic mechanisms to coordinate the spatiotemporal regulation of myelination . myelin is a product of vertebrate evolution that maximizes the efficiency and velocity of action potentials transmitted through nerve cells . demyelination as a result of disease or injury severely disrupts the efficient transmission of the action potential , ultimately resulting in a loss of function . to effectively treat these devastating conditions , it is essential to expand our knowledge concerning the generation and maturation of the myelin - forming cells and the processes that lead to myelination . in the cns , oligodendrocytes are responsible for the formation of myelin that surrounds axons . although most oligodendrocyte precursor cells ( opcs ) differentiate into myelinating oligodendrocytes , there remains a sizeable population of opcs that remain undifferentiated after the completion of myelination . in recent years , adult opcs have generated much interest as a reservoir of cells with the potential to self - renew , differentiate , and remyelinate the cns ( gensert and goldman , 1997 ; keirstead et al . , 1998 ; levison et al . , 1999 ; nishiyama et al . , 1999 ; horner et al . , 2000 ; although adult opcs are also thought to serve other functions within the nervous system ( paukert and bergles , 2006 ; nishiyama et al . , 2009 ) , their potential for recruitment into demyelinated lesions points to an ideal therapeutic role , as adult opcs represent an endogenous source of progenitor cells , making up 29% of the cns cell population ( dawson et al . , these cells seem to be distributed throughout the cns , remaining in the undifferentiated state even after other opcs differentiate and myelinate axons . current evidence suggests that these adult opcs express the same markers ( pdgfr- and ng2 ) as their developmental counterparts and appear morphologically similar ( nishiyama et al . , 1996 , 1999 ; wilson et al . , 2006 ; franklin and ffrench - constant , 2008 ) . it remains unclear as to why these particular progenitors differ from their myelinating counterparts during development and remain as uncommitted cells . understanding the developmental origins of adult opcs would begin to address whether these cells have the intrinsic capabilities to differentiate and myelinate as opposed to having a different cellular identity . are adult opcs derived from the same population as opcs during development , or are they a separate population of cells ? the answer appears complex , as during development , opcs are heterogeneous in their spatiotemporal origin ( fig . opcs arise from multiple regions of the ventricular zone in a sequential manner . the first wave of opcs that populate the forebrain originates from the medial ganglionic eminence and anterior entopeduncular area . these opcs are followed by a second wave from the lateral ganglionic eminence and caudal ganglionic eminence . these respective populations are identified not only by their spatiotemporal differences but also by their differential transcription factor expression ( kessaris et al . , 2006 ) . although these studies suggest the presence of heterogeneous opc populations , the majority of the opcs differentiate into oligodendrocytes and myelinate axons regardless of their origin . despite originating from multiple regions at different times throughout development , opcs are found evenly distributed throughout the adult brain in both gray and white matter alike ( fig . 1 , b d ) . developmental origins of opcs and the final distribution of adult opcs in the telencephalon . ( a ) schematic illustration outlining the origin of opcs in the telencephalon during development . as indicated by the arrows , opcs arise first from the medial ganglionic eminence ( mge ) at embryonic day 12.5 followed by the lateral ganglionic eminence ( lge ) several days later . cortically derived opcs appear soon after birth ( adapted from richardson et al . , 2006 ) . ( b ) despite their spatial and temporal differences in origin , opcs are evenly distributed throughout the adult brain and are found in regions such as the cortex ( ctx ) , corpus callosum ( cc ) , caudate putamen ( cp ) , and anterior commissure ( aco ) . myelin basic protein ( mbp ; green ) identifies the heavily myelinated white matter tracts . ( c and d ) magnified view of the adult brain , showing the presence of pdgfr-expressing adult opcs dispersed throughout both gray matter , as represented by the cortex , and white matter tracts such as the corpus callosum . additionally , compensatory mechanisms are observed when specific opc populations are eliminated , whereby opcs from different regions replace eradicated cells , resulting in normal oligodendrocyte and myelin phenotype ( kessaris et al . , 2006 ; given the interchangeable nature of these opcs despite spatiotemporal differences and the lack of evidence for adult opcs originating from a separate lineage , it is reasonable to assume that insight into the mechanisms responsible for differentiation during development may provide valuable information concerning the presence and potential utility of the adult opc . another fundamental question that needs to be considered is what normally happens during injury and demyelinating disease ? genetic fate - mapping studies show that adult opcs have the capacity to myelinate continuously throughout normal adult life ( dimou et al . , 2008 ; rivers et al . , 2008 however , in diseases such as multiple sclerosis , remyelination is limited to certain regions ( forming what are known as shadow plaques , where axons are thinly remyelinated ) and ultimately declining over time ( franklin , 2002 ) . which cells are responsible for these transient recoveries ? in the adult brain , oligodendrocytes are terminally differentiated and generally do not participate in remyelination ( keirstead and blakemore , 1997 ) . instead , opcs are found in demyelinated regions , and are thus able to mobilize to damaged areas ( keirstead et al . , 1998 ; scolding et al . , 1998 ; wolswijk , 1998 ; remyelination by adult opcs does not appear to be hampered by issues of access or recruitment . additionally , although adult opcs divide more slowly than their developmental counterparts ( shi et al . , 1998 ; tang et al . , 2000 ) , augmenting proliferation through increasing mitogens such as pdgf does not enhance remyelination ( woodruff et al . , 2004 ) . this further underscores opc differentiation as the barrier impeding myelin repair rather than the recruitment and/or migration of opcs . the fact that most of these adult opcs remain as precursors throughout development and after injury and/or disease begs several intriguing questions that are essential to understanding cellular differentiation and the mechanisms that maintain a precursor population in the adult nervous system . is it possible that the inhibitory mechanisms for maintaining a precursor pool are similar to that which prevents remyelination in the adult nervous system ? in this review , we will attempt to address these questions by integrating cell - autonomous differentiation events with microenvironmental cues and outline how these developmental processes may play a role after demyelination . although it is admittedly difficult to resolve this complex issue in a single review and will require further developmental and demyelination studies , reviewing current findings should aid in formulating the most effective and efficient means to determine the relative contribution between intrinsic and extrinsic forces . promoting remyelination in the cns requires the establishment of a conducive setting for differentiation and myelination . this greatly depends on understanding the fine balance of developmental signals as well as cues resulting from injury or disease . early efforts addressing the mechanisms involved in opc differentiation attempted to identify and dissect the individual components regulating this process by reducing the complexity of the environment . in vitro clonal density studies using purified opcs provided an intriguing case for a purely cell - autonomous mechanism . in the absence of environmental cues , the presence of an intrinsic opc differentiation program was observed where a timer mechanism was shown to regulate opc division and maturation ( raff , 2006 ) . in the presence of pdgf , a mitogen for opcs , proliferation was induced with the absence of differentiation . in the presence of both pdgf and thyroid hormone , opcs would divide six to eight times before differentiating , and progeny of a single clone grown separately would differentiate after approximately the same number of divisions as each other ( temple and raff , 1986 ; durand and raff , 2000 ) . this surprising finding suggested the presence of an intrinsic mechanism responsible for temporally controlling differentiation . although opcs were initially thought to monitor the number of divisions ( temple and raff , 1986 ) , it was later confirmed that the cells could somehow monitor time and not necessarily the number of divisions ( gao et al . , 1997 ) . although this mechanism still remains unclear , thyroid hormone acts through thyroid hormone receptor-1 to influence the activation of the timer , and various cyclin - dependent kinases , inhibitors , and other cell cycle regulatory proteins have been identified to influence both proliferation and differentiation ( durand et al . , 1998 ; these findings suggest that differentiation is not just a default mechanism of inhibited proliferation but is dependent on other intrinsic mechanisms within the cell . interestingly , opcs grown in the presence of pdgf over an extended period of time in vitro appear to take on characteristics of adult opcs , as both express similar markers and require a longer duration of time before differentiating ( tang et al . , 2000 ) . as an extension from these studies , thyroid hormone treatment to promote differentiation after demyelinating insult has shown some promise ( fernandez et al . contrary to these findings , when opcs are in direct contact with neurons , evidence for extrinsic regulation of differentiation prevails . these findings suggest the possibility that environmental cues may override any timer mechanism via opc / neuronal signaling within the dynamic cns milieu . overexpression of pdgf by neurons in vivo leads to hyperproliferation of opcs ; however , the generation and maturation of oligodendrocytes are not inhibited or delayed , resulting in a normal myelination phenotype ( calver et al . , 1998 ) . perhaps to perfectly myelinate the axons of the nervous system , a purely intrinsic mechanism may not be sufficient , as opcs need to adapt to the ever - changing environment of the cns , and contributions from the microenvironment consisting of other cell types may modulate the differentiation process . studies coculturing purified opcs with dorsal root ganglion neurons provide additional evidence for extrinsic regulation whereby the density of opcs influences differentiation . increasing the number of opcs seeded onto neurons accelerates the process of differentiation , and this effect is induced by spatial constraints exerted by neighboring opcs rather than a secreted or contact - mediated molecular cue ( rosenberg et al . , 2008 ) . addition of exogenous pdgf to the cocultures enhances differentiation rather than maintaining opcs in a proliferative state , as would be expected from the clonal density studies ( rosenberg et al . , 2008 ) . these findings imply the importance of the interaction between opcs and their surrounding environment and that differentiation is likely dependent on extrinsic cues that activate a transcriptional program for differentiation . understanding the balance of signals for these processes will provide valuable insight into the spatiotemporal control of differentiation during development and remyelination . in recent years , a great deal of research has been devoted to understanding the transcriptional program necessary for the generation of the oligodendroglial lineage . this investment has provided valuable insight , especially with the identification of the olig genes ( lu et al . , 2000 ; tekki - kessaris et al . , 2001 ; qi et al . , 2002 ; takebayashi et al . , olig1/2 are basic helix - loop - helix transcription factors that play multiple roles in determining the oligodendroglial lineage and are expressed in mature oligodendrocytes as well as in both developmental and adult opcs ( zhou et al . , 2000 ; ligon et al . , 2006 ) . these genes are responsive to sonic hedgehog , a ventrally expressed morphogen , which is both sufficient and necessary to induce olig gene expression for the generation of opcs ( lu et al . , 2000 ) . olig1/2 knockout mice fail to develop cells of the oligodendroglial lineage ( lu et al . , 2002 ; zhou and anderson , 2002 ) , and this is attributed specifically to olig2 function , as the olig2-null mouse displays a similar impairment in the generation of oligodendroglia and deficits in motor neuron specification ( lu et al . , 2002 ; takebayashi et al . , olig1 functions later in development , as the null mouse displays a specific defect in the maturation of oligodendrocytes while maintaining a seemingly normal pool of opcs throughout development ( xin et al . , 2005 ) . ectopic expression of olig2 results in an oligodendroglial fate rather than a neural fate with the induction of sox10 , a high mobility group box transcription factor expressed by oligodendrocytes ( lu et al . , . interestingly , the coexpression of olig2 with nkx2.2 induces oligodendrocyte differentiation ( sun et al . , 2001 ; zhou et al . olig1 participates in differentiation by up - regulating several myelin genes , including mbp , plp , and mag as well as suppressing gfap , an astrocytic gene ( xin et al . , 2005 ; li et al . , 2007 ) the localization of olig1/2 is observed in the nucleus of opcs during development ; however , although olig2 remains in the nucleus of opcs in the adult mouse , olig1 is found to be cytoplasmic ( arnett et al . , 2004 ) . could the repression of olig1 function in a population of opcs give rise to the adult precursor cell , and what mechanisms selectively regulate this repression ? in a murine demyelination model and within tissue from multiple sclerosis patients , olig1 is translocated into the nucleus of opcs as in development and may be associated with oligodendrocyte differentiation in the repair process , and as anticipated , remyelination is impaired in the olig1 knockout mouse ( arnett et al . although these studies illustrate the importance of olig genes in opc fate and differentiation , the extracellular pathways coupled to differentiation remains to be elucidated . by screening for molecules dynamically regulated in the olig1 knockout mouse , gpr17 , a gi protein  coupled orphan receptor , was identified as a negative regulator of oligodendrocyte differentiation ( chen et al . , 2009 ) . gpr17 is related to p2y ( purinergic ) and cysteinyl  leukotriene receptors and can be activated by nucleotides and inflammatory mediators ( ciana et al . , 2006 ) . further studies demonstrate that gpr17 is up - regulated in mouse oligodendrocytes after demyelination , and analysis of human multiple sclerosis plaque tissue by quantitative pcr reveals an increase in gpr17 expression . to further investigate the role of this potential receptor , mice with sustained gpr17 overexpression in oligodendrocytes overexpressing gpr17 in vitro results in the nuclear localization of id2/4 , which complex with olig1/2 and inhibit opc differentiation ( samanta and kessler , 2004 ; chen et al . , 2009 ) . conversely , knocking out gpr17 results in precocious myelination and accelerated opc differentiation ( chen et al . , 2009 ) . gpr17 is a novel putative extracellular receptor that inhibits opc differentiation , and its expression in adult opcs after demyelination deems it a valuable potential therapeutic candidate . identifying the exogenous ligand for this receptor would provide a valuable link between the environmental and transcriptional control of oligodendrocyte differentiation . to complicate things even further , although the process of opc differentiation undoubtedly requires transcriptional changes , epigenetic mechanisms also influence opc differentiation and can do so in a spatiotemporal - specific manner ( li et al . , 2009 ) . additionally , several of these studies implicate conserved signaling pathways for adult opcs after demyelinating insult . the transition from a precursor cell to a mature , myelinating oligodendrocyte requires a coordinated effort and can be achieved by modulating transcription via dna modification . these epigenetic states can be heritable and are susceptible to environmental influences , which may allow for the dynamic interaction between intrinsic and extrinsic factors to occur . multiple sclerosis is a progressive disease , and the severity worsens with age ( compston and coles , 2008 ) . in correlation , recent findings demonstrate a decline in the efficiency of myelin repair in a cuprizone - induced model of demyelination in an age - dependent manner ( shen et al . , this age - related decrease is attributed to epigenetic regulation of adult opcs dependent on the recruitment of histone deacetylases ( hdacs ; popko , 2008 ; shen et al . , 2008 ) . administering hdac inhibitors to young and older mice result in different remyelination efficiencies ( shen et al . , 2008 ) . hdacs normally remove acetyl groups from histones to allow for the compaction of chromatin , which subsequently silences transcription . recent evidence suggests that this is the result of the repression of pathways that normally prevent differentiation from occurring ( popko , 2008 ; shen et al . , 2008 ; two independent studies demonstrate that wnt signaling is responsible for repressing opc differentiation ( fancy et al . , 2009 ; li and richardson , 2009 ; rosenberg and chan , 2009 ; ye et al . , 2009 ) . the wnt signaling pathway usually prevents the degradation of -catenin , and knocking out hdac1/2 in oligodendroglial cells results in the stabilization of -catenin in the nucleus , which in turn represses olig2 ( ye et al . , 2009 ) . these findings also demonstrate the direct association of hdac1/2 with tcf4/tcf712 and -catenin . signaling through the wnt pathway can interfere with this interaction and inhibit opc differentiation ( li and richardson , 2009 ; ye et al . , 2009 ) . both studies report that the constitutive expression of -catenin impairs opc differentiation and remyelination ( fancy et al . , 2009 ; ye et al . , 2009 ) . knocking out adenomatous polyposis coli , a -catenin antagonist , results in a similar phenotype ( fancy et al . , 2009 ) . furthermore , a demyelination microarray screen identifies the increased expression of tcf4/tcf712 in the normal developing human cns and tissue from multiple sclerosis lesions ( fancy et al . , 2009 ) . tcf4/tcf712 was originally found to be repressed by transcription factor ying yang 1 , which also suppresses id4 , another transcriptional inhibitor of opc differentiation ( he et al . , 2007 ) . collectively , these findings highly suggest that mechanisms which control differentiation during development likely influence differentiation after injury and/or disease . more importantly , the wnt pathways provide a means of extracellular input , which further broadens our appreciation for the complexity of coordinating extrinsic and intrinsic mechanisms ( rosenberg and chan , 2009 ) . neuronal communication is essential for regulating opc development , including the timing of differentiation and myelination . during development , the axon expresses numerous inhibitory cues preventing opc differentiation to ensure the proper spatial arrangement of oligodendrocytes and temporal control of myelination along axon tracts . however , many of these same extrinsic signals expressed along axons are reexpressed during demyelinating conditions , which may impair efforts to promote remyelination . identifying these molecular cues and understanding how they influence differentiation of opcs may provide new insight into providing a permissive environment for myelin repair . the neural cell adhesion molecule ( ncam ) is expressed ubiquitously by nearly all neurons , and axons express the polysialylated ( psa ) form during development before the onset of myelination ( jakovcevski et al . , 2007 ) . this modification reduces homophilic interactions between ncams as a result of the negative charge and/or hydration volume of the psa ( kleene and schachner , 2004 ) . in addition , psa - ncam can modulate heterophilic interactions with other glycans , such as heparan sulfate proteoglycans , which are also expressed by opcs ( winkler et al . , 2002 ) . correlative studies report a decrease in expression of psa - ncam before the onset of oligodendrocyte myelination , and prematurely eliminating psa - ncam from neurons in vitro enhances differentiation and myelination ( charles et al . , 2000 ) , suggesting an inhibitory role when present ( jakovcevski et al . , as adhesion is a process that is required for numerous cellular processes , including migration and other forms of cell  cell interaction , adult opcs may require a permissive substrate lacking psa - ncam to differentiate and remyelinate . indeed , psa - ncam is reexpressed in multiple sclerosis lesions but not in regions where remyelination occurs ( charles et al . , 2002 ) . another axonal inhibitor of opc differentiation is the notch receptor jagged1 ( wang et al . , 1998 ) . notch is an evolutionarily conserved transmembrane protein , whereby activation through its putative receptors jagged and delta results in the cleavage of its intracellular domain . upon cleavage , notch is translocated to the nucleus and modulates transcription to influence cell fate and differentiation ( kopan and ilagan , 2009 ) . notch1 is thought to act through hes5 , a basic helix - loop - helix transcription factor , which in turn suppresses transcription of myelin genes ( wang et al . , 1998 ; liu et al . , 2006 ) . knocking out notch1 in vivo results in premature differentiation and ectopic oligodendrocyte formation in the gray matter ( genoud et al . , 2002 ) . inhibiting -secretase ( the protease involved in notch1 cleavage ) in vitro also enhances differentiation ( watkins et al . , 2008 ) . targeted deletion of notch1 in olig1-expressing opcs results in precocious differentiation , and consistent with its inhibitory effect on opc differentiation during development , remyelination is enhanced in this mouse model ( zhang et al . , 2009 ) . as adult opcs 1998 ) , further investigation is required to determine the possible role for notch signaling in maintaining adult opcs and the lack of differentiation and myelination after demyelinating insult . a potent example of an axonal inhibitor of oligodendrocyte differentiation that has been examined in various demyelinating animal models is the leucine - rich repeat and ig domain  containing , nogo receptor  interacting protein ( lingo-1 ; mi et al . , 2005 , 2007 , 2008 , 2009 ; lingo-1 antibody has proved to enhance functional recovery and remyelination after experimental autoimmune encephalomyelitis , lysolecithin treatment , and after cuprizone - induced demyelination ( mi et al . although these results illustrate great therapeutic potential , the mechanisms that control this inhibition remain unclear . it seems that both oligodendrocytes and neurons express lingo-1 , and disruption of lingo-1 functions on oligodendrocytes or neurons , respectively , is sufficient to promote differentiation and myelination ( mi et al . , 2005 ; lee et al . additionally , lingo-1 activates the rho family gtpase rhoa and decreases fyn expression and activation ( mi et al . , 2005 ) . these intracellular signaling molecules further studies concerning the developmental regulation of the axonal expression of lingo-1 should illuminate this paracrine relationship between axons and opcs , which may also be relevant after injury and disease . connective tissue growth factor ( ctgf ) is another paracrine signal expressed and secreted by neurons to inhibit opc differentiation . ectopic expression of ctgf in vivo through adenovirus transduction reduces the number of oligodendrocytes formed during development ( stritt et al . , ctgf is thought to sequester and thereby antagonize the function of insulin - like growth factor 1 , which has been implicated in stimulating opc differentiation ( mcmorris et al . , 1986 ; hsieh et al . , 2004 ) . suppression of ctgf relies on the transcription factor serum response factor ( srf ) , permitting differentiation during development ( stritt et al . , 2009 ) . srf is a transcription factor with multiple binding partners such as tcfs and myocardin - related transcription factors ( mrtfs ) and can be activated by growth factors , such as ngf and brain - derived neurotrophic factor , or through neuronal activity ( wickramasinghe et al . , 2008 ; knll and nordheim , 2009 ) . deletion of srf specifically in neurons results in an increase in the number of opcs and inhibits the maturation and differentiation processes ( knll and nordheim , 2009 ; stritt et al . , these results clearly illustrate the shared importance and reciprocal nature of understanding transcriptional , epigenetic , and the extrinsic signals that modulate oligodendrocyte maturation . by fully considering the mechanisms required for the activation of these processes , we hope to gain valuable insight into establishing an environment conducive for opc differentiation during development and remyelination . one of the most fundamental questions in biology is whether it is possible to resolve pathological states by recapitulating development . the opc is a prototypical cell for answering this question , as an abundant number of endogenous undifferentiated precursors exist in the adult nervous system . additionally , the simplicity in the binary decision to become a terminally differentiated oligodendrocyte or remain a precursor cell reduces the complexity when addressing cell fate decisions . making the commitment to differentiate during development is a complex process , as it requires the coordination of transcriptional machinery in conjunction with epigenetic regulation within the cell . ongoing research has also provided evidence for the impact of extrinsic factors on opc differentiation . curiously , many of these environmental influences appear to be inhibitory in nature , with the axon delaying opc differentiation rather than promoting it . 2 summarizes the molecular components discussed in this review , with all of them playing a role during developmental opc differentiation , and many of these inhibitory factors , originating from both the axon and within the opc itself , appear to prevent adult opcs from reaching their potential to participate in myelin repair . both contact - mediated cues and secreted factors participate in inhibiting differentiation , although there is still much to learn as to how these environmental signals converge upon intracellular pathways as well as transcriptional regulators responsible for maintaining opcs in an undifferentiated state ( fig . solid arrows indicate contact - mediated interactions such as jagged1 expressed on axons acting through notch1 on opcs , leading to the suppression of myelin genes via hes5 . dashed arrows indicate secreted molecules such as ctgf from the neuron and wnt from a yet - unidentified source . although its ligand has not been determined , gpr17 expressed by opcs is likely sensitive to environmental signals . furthermore , unlike the peripheral nervous system , the cns has no capacity for removing inhibitors that prevent differentiation and remyelination ( vargas and barres , 2007 ) . it is not clear as to why there are numerous inhibitory cues and few inductive factors ; perhaps this allows for the finer control of the differentiation process or even for the maintenance of adult precursors . despite our lack of understanding , it appears that overriding these inhibitory cues expressed during injury and disease may be the first practical step to understanding restoration . conversely , a concerted effort to identify inductive cues will also enrich our understanding of the balance of signals involved in opc differentiation during development and remyelination . 3 illustrates a summary of this review , in which yet - unidentified inductive cues for opc differentiation are represented by the school of oligodendrocyte precursors heading toward the dam . the barrier itself is an analogy for inhibitory cues and is composed of myriad cell - autonomous and microenvironmental signals . during injury and disease , we propose that the removal of the barrier ( inhibitory cues ) is necessary in order for remyelination to occur , represented by oligodendrocytes downstream of the reservoir . likewise , if one fills the dam high enough through inductive means , can one overcome the barricade , i.e. , balance of induction and inhibition ? also , what determines the fate of individual opcs , making one more likely to remain uncommitted in adulthood , whereas others will terminally differentiate ? our illustration can not represent the intricate geometry of the cns where adult opcs seem to reside throughout . however , the seemingly arbitrary distribution of adult opcs can be deceiving ; in fact , the extrinsic influences discussed in this review may be working collectively through constructing unique , dispersed microenvironments where adult opcs inhabit . even though occam s razor would suggest otherwise , the cns has to rely on complex and robust mechanisms for maintaining precursor cells , and this may require a dynamic array of intercellular interactions . if this is the case , it will be challenging to identify the components involved in adult opc maintenance within the complex cns neuropil . grasping the elusive nature of these endogenous precursors will also allow us to exploit their potential during injury and disease . a proposed model for the maintenance of adult opcs . they are inhibited from differentiating into oligodendrocytes ( green ) by several cell - autonomous ( intrinsic ) and microenvironmental ( extrinsic ) inhibitory cues . presumably unidentified inductive cues may act to overcome the inhibitory barrier and allow differentiation to occur .
the development and maturation of the oligodendrocyte requires a series of highly orchestrated events that coordinate the proliferation and differentiation of the oligodendrocyte precursor cell ( opc ) as well as the spatiotemporal regulation of myelination . in recent years 
 , widespread interest has been devoted to the therapeutic potential of adult opcs scattered throughout the central nervous system ( cns ) . in this review , 
 we highlight molecular mechanisms controlling opc differentiation during development and the implication of these mechanisms on adult opcs for remyelination . 
 cell - autonomous regulators of differentiation and the heterogeneous microenvironment of the developing and the adult cns may provide coordinated inhibitory cues that ultimately maintain a reservoir of uncommitted glia .