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FEBS Letters 585 (2011) 3813–3820

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Review Promoting repair and return of function in multiple sclerosis

Jingya Zhang a,b,c, Elisabeth G. Kramer a,b,c, Linnea Asp a,b,c, Dipankar J. Dutta a,b,c, Kristina Navrazhina a,b,c, Trinh Pham a,b,c, John N. Mariani a,b,c, Azeb Tadesse Argaw a,b,c, Carmen V. Melendez-Vasquez d, ⇑ Gareth R. John a,b,c,

a Corinne Goldsmith Dickinson Center for MS, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA b Department of Neurology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA c Friedman Brain Institute, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA d Department of Biological Sciences, Hunter College, 695 Park Avenue, New York, NY 10065, USA

article info abstract

Article history: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Conduction block in Received 7 July 2011 demyelinated axons underlies early neurological symptoms, but axonal transection and neuronal Revised 8 August 2011 loss are believed to be responsible for more permanent chronic deficits. Several therapies are Accepted 9 August 2011 approved for treatment of relapsing-remitting MS, all of which are immunoregulatory and clinically Available online 18 August 2011 proven to reduce the rate of lesion formation and exacerbation. However, existing approaches are Edited by Richard Williams, Alexander only partially effective in preventing the onset of disability in MS patients, and novel treatments Flügel and Wilhelm Just to protect myelin-producing oligodendrocytes and enhance myelin repair may improve long-term outcomes. Studies in vivo in genetically modified mice have assisted in the characterization of Keywords: mechanisms underlying the generation of neuropathology in MS patients, and have identified Multiple sclerosis potential avenues for oligodendrocyte protection and myelin repair. However, no treatments are Demyelination yet approved that target these areas directly, and in addition, the relationship between demyelina- Axonal transection tion and axonal transection in the lesions of the disease remains unclear. Here, we review transla- Regeneration tional research targeting oligodendrocyte protection and myelin repair in models of autoimmune Neuroprotection demyelination, and their potential relevance as therapies in MS. Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

1. Introduction rate of axonal transection and neuronal loss. Moreover, such ap- proaches could be employed in combination with currently avail- Multiple sclerosis (MS) presents in its initial form most com- able immunoregulatory treatments, for additive or synergistic monly in young adults, especially women [1]. Conduction block in effects [13]. However, all therapies currently approved for the treat- demyelinated axons is understood to be responsible for early neuro- ment of relapsing-remitting MS are immunoregulatory, and do not logical deficits [1], while axonal transection and neuronal loss directly address oligodendrocyte protection and remyelination. underlie more permanent later disability [2]. Endogenous myelin These areas are thus the subject of intense current research focus. repair is known to exist in early lesions, and leads to return of con- The first neuroprotectant approved for use in MS will represent a duction and function [3,4], but this process gradually fails as the dis- significant advance in the field, and may also have far-ranging impli- ease progresses [5,6]. For CNS remyelination to occur, progenitors of cations for the treatment of other neurodegenerative disorders. myelin-forming oligodendrocytes must be recruited into demyeli- Studies in knockout mice and conditional mutants have acceler- nated areas, and then subsequently differentiate into mature, mye- ated our understanding of lesion pathogenesis in MS models, and linating cells which each typically wrap multiple axons [7–9]. have revealed pathways controlling oligodendrocyte survival and Consistent with this model, committed oligodendrocyte progenitors myelin repair [14]. Factors implicated in protection of oligodendro- (OPCs) have been detected in developing brain, normal adult human cytes or remyelination include , gp130 neurotrophic brain, MS lesions and animal models [5,10–12]. Studies suggest that , -like growth factors, and retinoid receptor signal- approaches protective for oligodendrocytes and that enhance mye- ing. By contrast, pathways shown to restrict repair have included lin repair are likely to improve long-term outcomes and reduce the LINGO-1, bone morphogenetic proteins, and canonical Wnt and Notch signaling [13–15] (Fig. 1). However, despite these advances, no therapies have yet been approved that target these areas in MS ⇑ Corresponding author at: Corinne Goldsmith Dickinson Center for MS, Mount patients. Moreover, the relationship between demyelination and Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA. Fax: +1 axonal transection remains unclear, as does the potential for 212 348 1310. remyelination to restrict neuronal loss in MS lesions. E-mail address: [email protected] (G.R. John).

0014-5793/$36.00 Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2011.08.017 3814 J. Zhang et al. / FEBS Letters 585 (2011) 3813–3820

Fig. 1. Regulation of oligodendrocyte progenitor mitosis, differentiation and apoptosis. An outline of the progression of oligodendrocyte differentiation, from neural progenitor (left), through specified oligodendrocyte progenitor, to mature postmitotic oligodendrocyte capable of myelin formation (right). Mechanisms of action are shown of factors that augment (lower panel, blue/green) or restrict (upper panel, red) the number of mature myelinating cells. Retinoid X receptor signaling and the gp130 cytokines CNTF, IL-11 and LIF promote oligodendrocyte maturation (lower panel). The gp130 cytokines also improve the viability of mature oligodendrocytes or their precursors, a property they share with the insulin-like growth factors IGF-1 and IGF-2, and the , NT-3. Additionally, NT-3 potentiates precursor proliferation. At later stages of maturation, 1 type III-ErbB signaling facilitates axonal ensheathment and myelin wrapping. Conversely, bone morphogenetic proteins inhibit oligodendrocyte lineage specification and subsequent progenitor differentiation (upper panel). Canonical Notch and Wnt signaling restrict maturation, and maintain the size of the progenitor pool.

Here, we review potential approaches for oligodendrocyte pro- STAT-1 and STAT-3 [27]. Soluble -6 (IL-6) receptor/IL-6 tection and remyelination in MS and its animal models. Obstacles fusion protein similarly induces STAT1/3 phosphorylation and en- to development of novel therapies in these areas will also be hances differentiation of rodent oligodendrocyte progenitor cul- discussed. tures in vitro [28]. CNTF and LIF also promote oligodendrocyte survival [29,30]. CNTFÀ/À or LIFR+/Àgp130+/À mice with the MS 2. Pathways promoting oligodendrocyte viability, maturation model, experimental autoimmune encephalomyelitis (EAE), dis- and myelination play exacerbated disease and increased oligodendrocyte apoptosis, although LIFÀ/À mice also show an attenuated late phase of disease 2.1. Gp130 neurotrophic cytokines [31–33]. Administration of CNTF is not sufficient to promote oligo- dendrocyte remyelination in demyelinating lesions induced by Gp130 was originally identified as a signal transducing compo- microinjection of ethidium bromide in vivo [34], although trans- nent that associated with the receptor (IL-6R) follow- plantation of adult oligodendrocyte precursor cells expressing ing ligand binding [16]. However, subsequent work defined gp130 CNTF has been reported to promote remyelination and functional as a receptor shared by all members of a large pleiotropic family of recovery following traumatic injury to the spinal cord [35]. More- cytokines. The family includes IL-6, IL-11, IL-27, oncostatin M over, CNTF administration does protect mice from inflammatory (OSM), leukemia inhibitory factor (LIF), cardiotrophin 1(CT-1), pathology in EAE for the duration of treatment [36]. Endogenous and ciliary neurotrophic factor (CNTF) [17]. IL-6R and IL-11Ra in- LIF protects mature oligodendrocytes from demyelination and also duce gp130 homodimerization [18], whereas LIF, CNTF, oncostatin enhances remyelination, and exogenous LIF has also been used M and CT-1 binding lead to heterodimerization with the LIF recep- successfully to limit the consequences of oligodendrocyte damage. tor (LIFR) [19]. Either homo- or heterodimerization triggers the [37,38]. activation of Janus kinase (JAK) kinases [20,21], which Taken together, these findings implicate CNTF and LIF signaling leads to - and cell type-specific phosphorylation and nu- as potential neuroprotective and pro-regenerative approaches for clear translocation of Stat transcription factors [22]. Stat-indepen- therapy of MS and other demyelinating diseases. However, despite dent signaling has also been described [22]. successes of CNTF in studies in animal models of neurodegenera- Members of the gp130 cytokine family play important roles in tion [25,39], testing in neurodegenerative conditions in human pa- the immune, hemopoietic, cardiovascular and reproductive system tients was unsuccessful in [40,41], and these failures have [22]. Importantly, the family has also demonstrated strong trophic significantly dampened enthusiasm for clinical trials in MS. Inter- functions within the CNS, notably neuroprotection. For example, estingly, however, the reasons for the ineffectiveness of CNTF in mice deficient in CNTF or CNTFR, and CT-1À/À mice, display loss human trials have not been fully investigated, and it remains of motoneurons [23,24], and CNTF is protective in neurodegenera- possible that lack of access to the CNS parenchyma through the tive models in primates [25]. These reports have understandably blood-brain barrier may be responsible in part or whole for these stimulated research examining mechanisms underlying these negative findings. effects, and the translational potential of gp130 signaling in CNS disease. Relevant to this review, investigation of effects on oligo- 2.1.2. IL-11 – oligodendrocyte protection and immunoregulation dendrocytes has focused primarily on CNTF, LIF and IL-11. Experiments in primary human cultures and mathematical modeling in rodent oligodendrocyte progenitors have shown that 2.1.1. Neuroprotective roles of CNTF and LIF IL-11 enhances oligodendrocyte survival and maturation, and that CNTF promotes the final maturation of oligodendrocyte progen- these effects may be more potent than those of LIF [42–44] (Fig. 1). itors, and via gp130 and Jak signaling [26] leading to activation of IL-11 treatment is also associated with increased myelin formation J. Zhang et al. / FEBS Letters 585 (2011) 3813–3820 3815 in rodent CNS cocultures [43], and this effect appears to be due to quences of recombinant IGF-1 therapy in MS patients failed to pro- predominantly to improved survival of oligodendrocyte lineage duce statistically significant findings [54]. Similar to trials using cells [44]. Interestingly, in contrast to the predominantly neuro- CNTF, the extent to which this result was attributable to inability protective effects of CNTF and LIF, IL-11 displays significant immu- of IGF-1 to cross the BBB is unclear [54]. Restrictions in CNS access noregulatory actions. Studies in vivo have shown that and issues with cell type specificity may once again represent a administration of recombinant IL-11 decreases the clinical course confound in clinical trial design in the case of IGF-1, confusing and neuropathology of EAE, whereas IL-11RaÀ/À mice display in- interpretation for another potentially neuroprotective and regen- creased demyelination and oligodendrocyte loss, and delayed erative therapeutic pathway in MS. remyelination, accompanied by exacerbated CNS inflammation [42,44]. While IL-11 directly increases the viability of oligodendro- 2.3. Neurotrophins cyte lineage cells, its immunoregulatory properties depend on pro- apoptotic actions on antigen-presenting dendritic cells (DCs) The neurotrophins (NTs) are a family of soluble mediators that [42,44]. Interestingly, both effects are dependent on lineage- include nerve (NGF), brain-derived neurotrophic fac- specific activity of the transcription factors Stat1 versus Stat3. In tor (BDNF), neurotophin-3 (NT-3) and neurotophin-4/5 (NT-4/5) both cell types, Stat3 is anti-apoptotic, whereas Stat1 promotes cell [55]. Members of the family interact with two classes of trans- death. However, following IL-11 treatment, activity of Stat3 membrane receptors: the receptor tropomyosin- predominates over its relative in oligodendrocytes, whereas the related kinases (Trk), and the TNF-a receptor superfamily p75 pro-apoptotic effects of Stat1 prevail in DCs [44]. Collectively, these neurotrophin receptor p75NTR [56]. Each neurotrophin displays data reveal novel mechanisms underlying the actions of a neuro- selective high-affinity interaction with specific Trk receptors, with protective and immunoregulatory member of the gp130 cytokine NGF binding to TrkA, BDNF and NT-4/5 to Trk-B, and NT-3 to Trk-C. family in inflammatory demyelinating disease, and suggest new All bind additionally to p75NTR. The precursor form of NTs are avenues to enhance oligodendrocyte survival and restrict CNS known as proneurotrophins, and these are also found in abundance inflammation in MS. in the brain, and are believed to be biologically active [57,58]. Neurotrophins were originally characterized as playing impor- 2.2. Insulin-like growth factors (IGFs) tant roles in the development and maturation of specific popula- tions of CNS neurons [56]. However, they have also been found IGFs are neuroprotective trophic factors for cells of the oligo- to exert strong effects on myelinating glia and on earlier uncom- dendrocyte lineage [45], which encompass IGF-1 and IGF-2, and mitted progenitors, and these will be summarized here, together the regulatory IGF-binding proteins (IGFBPs). IGF-1 and IGF-2 sig- with their translational potential. nal through the IGF-1 receptor (IGF-1R) and IGF-2 receptor (IGF- 2R), respectively. Interestingly, IGF-1 is expressed at high level in 2.3.1. Neurotrophins and myelination neuron-rich areas of the brain, whereas IGF-2 is found at high lev- Studies have revealed NGF as regulating myelination of TrkA- els in myelinated tracts, and is the most abundant IGF in the CNS expressing dorsal root ganglion (DRG) neurons by both Schwann [46]. cells and oligodendrocytes in vitro, and have demonstrated that The phenotypes of mutants for the IGFs and their binding pro- these effects are mediated via direct interaction between NGF teins have provided important insights into the roles of members and neuronal TrkA receptors [59]. However, the interaction be- of the family in CNS development. For example, mice deficient tween NGF and TrkA leads to differential outcomes in the two for IGF-1 display reduced brain size, hypomyelination, reduced oli- co-culture types, promoting myelin formation by Schwann cells godendrocyte numbers and severe neuronal loss [47]. IGF-1 exerts but inhibiting oligodendrocyte myelination [59]. Thus, the impact neurotrophic and neuroprotective effects in vitro, and enhances of NGF on myelin formation includes important effects on neurons. neuronal survival and differentiation. By comparison, the brains However, additional investigations have shown that NGF also en- of transgenic mice overexpressing IGF-1 are 55% larger than con- hances oligodendrocyte survival, although it does not promote trols, and show increased cell number and size, and myelin content OPC proliferation unless coadministered with the mitogen fibro- in these mice is increased by 130% [48]. Moreover, the percentage blast growth factor [60]. of myelinated axons and myelin thickness are reduced in trans- Unlike NGF, the impact of NT-3 on myelin formation encom- genic animals overexpressing IGFBP-1, [49]. IGF-1 enhances oligo- passes potent glial effects. An important role in promoting myeli- dendrocyte survival and supports differentiation in vitro, which is nation is supported by the phenotype of NT-3 or TrkC-deficient accompanied by enhanced process branching and increased pro- mutants. NT-3 is essential for cardiovascular development and so duction of myelin proteins [45,50]. most NT3À/À mice die within 3 weeks of birth [61], but at postnatal Suggesting relevance to de- and remyelination, injection of day 0 (P0) mice of this genotype exhibit a 35% reduction in the IGF-1 into animals with EAE reduces the numbers and area of number of OPCs in the ventral spinal cord [62]. In addition, quan- demyelinating lesions [51]. IGF-1 therapy has also been reported tification of more mature oligodendrocyte lineage cells reveals to increase the number of axons containing regenerating myelin significant reductions in the number of differentiated GalC+ oligo- segments, reduce blood–spinal cord barrier permeability, and dendrocytes (28% reduction) and myelin basic protein (MBP) enhance myelin expression, and these changes have been mRNA+ (27% reduction) cells in spinal cords of NT-3–/– animals shown to be associated with rapid clinical and pathological recov- [62]. TrkCÀ/À mutants display comparable findings [62]. Experi- ery in the treated animals. However, although subsequent studies ments in vitro have described the effects of NT-3 on oligodendro- in chronic relapsing EAE have shown transient clinical ameliora- cyte survival and proliferation, in addition to promoting the tion and low-level remyelination after IGF-1 administration during clonal expansion of oligodendrocyte progenitor cells when com- the acute phase of disease, samples from acute phase-treated ani- bined with the mitogen platelet-derived growth factor [29,63] mals did not show potentiated remyelination at chronic time (Fig. 1). In addition, NT-3 has been shown to enhance myelination points [52]. in co-cultures of OPCs and neurons, by inducing differentiation of The translational potential of IGF-1 also remains unfulfilled in OPCs into myelin-forming cells [64], and NT-3-transfected OPCs MS. In active lesions from MS patients, IGF-1 expression localizes show increased MBP expression and enhanced myelination of hip- to reactive astrocytes, while IGF-2 is expressed by activated pocampal neurons [65]. In the optic nerve, neutralization of NT-3 microglia [53]. However, a clinical trial examining the conse- by injection of hybridoma cells secreting anti-NT-3 antibody 3816 J. Zhang et al. / FEBS Letters 585 (2011) 3813–3820 abrogates OPC proliferation and depletes the population of mature tiation and myelination [80–82], and heterozygous NRG1 type III oligodendrocytes [63]. mutants are hypomyelinated [83]. Oligodendrocytes and their pro- Interestingly, while NGF, NT-3 and BDNF have all been shown to genitors express ErbB2, ErbB3 and ErbB4, and these two receptors promote differentiation of basal forebrain oligodendrocytes, only have been suggested to control CNS myelination in vivo, [81]. NGF and NT-3 promote maturation of cortical oligodendrocytes Importantly, however, analysis conditional null mutants lacking [66]. Whereas studies suggest relevance of BDNF in regulating NRG1 with onset at different stages of neural development has re- myelination in vivo, the underlying mechanism is incompletely vealed that the CNS in these animals myelinates normally [84]. characterized. Most BDNFÀ/À mice show perinatal lethality, but a Experiments using disruption of ErbB signaling have produced minority live for up to 21 days [67], and at P13 numbers of retinal similar findings. While oligodendrocytes express ErbB2 and ErbB4 ganglion cells and the thickness of the retina are normal in these homo/heterodimers, ErbB2 lacks ligand-binding activity. However, survivors, but the proportion of myelinated axons in the optic mice conditionally null for both ErbB3 and ErbB4 receptors myeli- nerve is reduced, by approximately 50% [67]. This reduction is nate normally in the absence of oligodendroglial neuregulin signal- maintained at P21, but is accompanied at this timepoint by a ing [84]. Interestingly, however, transgenic overexpression of reduction in optic nerve axon diameter, suggesting that BDNF–/– NRG1 type I or NRG1 type III leads to significant CNS hypermyeli- mice may develop with a greater proportion of small unmyelinated nation [84]. Thus, collectively these data suggest that NRG1/ErbB axons. Moreover, the hippocampus and cortex of BDNFÀ/À mice signaling plays different roles in myelin formation in the PNS ver- display reduced levels of MBP and PLP mRNA [68]. However, since sus the CNS. Whereas neuregulin signaling regulates oligodendro- the phenotype of these mice combines alterations in both neuronal cyte development and central myelin formation, control of and glial compartments, it is not yet clear whether these events are oligodendrocyte myelination is significantly NRG/ErbB-indepen- mediated by BDNF acting directly on oligodendrocytes, or indi- dent. Thus, these findings significantly impact the translational po- rectly, via effects on neuronal TrkB receptors. tential for this pathway as a therapeutic avenue for myelin repair in MS. 2.3.2. Translational potential of neurotrophins Translational studies have explored the potential of neurotro- 2.5. Retinoid X receptor signaling phins to establish functional recovery following nerve injury and demyelination. Experiments in which fibroblasts expressing either Retinoid X receptors (RXRs) are nuclear receptors with impor- BDNF or NT-3 have been transplanted into rodent spinal cords after tant functions in regulation of cell proliferation and differentiation injury have resulted in enhanced axonal growth, OPC proliferation [85]. RXRa, RXRb and RXRc can form homodimers or heterodimers and myelin formation [69]. Moreover, transplantation of Schwann with other nuclear receptors, including retinoic acid receptors, thy- cells expressing BDNF or NT-3 into demyelinated spinal cords leads roid hormone receptors, vitamin D receptors and peroxisome pro- to increased OPC proliferation and differentiation, remyelination liferator activator proteins, to control transcription of target . and locomotor recovery in mice [70]. Interestingly, studies have Suggesting potential translational relevance, all three members of also implied a functional role for BDNF in promoting axonal protec- the RXR family are highly expressed in lesions following CNS injury tion in autoimmune demyelination [71]. Remyelination and [86]. Interestingly, recent work has implicated RXRs as positive functional recovery have also been demonstrated following trans- regulators of OPC differentiation [87]. Studies have shown that plantation of glial-restricted precursor cells (GRPs) expressing a RXRc is highly expressed in oligodendrocyte lineage cells during multi-neurotrophin of BDNF and NT-3 into the CNS of rats sub- CNS remyelination in rodents, and that in acute and remyelinating jected to spinal cord injury [72]. However, although these reports MS lesions RXRc is highly expressed by oligodendrocyte lineage have provided evidence that neurotrophins are effective at pro- cells, macrophages and astrocytes, but that expression is very moting spinal cord regeneration, the contributions of effects on low in chronic inactive lesions [87]. Importantly, knockdown of neurons versus glia to these outcomes are not yet fully established. RXR-c inhibits oligodendrocyte differentiation in vitro. Moreover, mice that lack RXR-c display efficient repopulation of demyelinat- 2.4. type III ed lesions with OPCs, but delayed differentiation of these cells into mature oligodendrocytes [87]. In addition, administration of the Members of the neuregulin 1 (NRG1) family play important RXR agonist 9-cis-retinoic acid to aged rats after demyelination re- roles in development and maintenance of the central and periphe- sults in an increase in remyelinated axons. Collectively, these data ral nervous systems [73]. They are ligands for Erb receptor tyrosine implicate RXR-c as a regulator of OPC maturation and remyelina- kinases located on glial cells, and more than 16 isoforms are tion, and suggest it as a future avenue for regenerative therapy in known, encoded through multiple promoter utilization and alter- MS. native splicing [73,74]. These include neu differentiation factor (NDF), heregulin, acetylcholine receptor inducing activity (ARIA), and glial growth factor (GGF). All members of the family share a 3. Inhibitors of maturation and myelination unique (EGF)-like domain, required for receptor activation. While committed oligodendrocyte progenitors (OPCs) have The best understood function of NRG1 is in control of peripheral been detected in adult human brain and remyelination has been myelination, where axonal NRG1 is essential for neuronal survival, demonstrated in MS lesions [5,10–12], the capacity for regenera- and for viability, proliferation and differentiation of myelinating tion in MS appears limited [88]. The mechanisms underlying this Schwann cells [75]. In the developing PNS, a threshold level of ax- failure of repair are incompletely characterized [89,90]. Interest- onal NRG1 type III expression is required to induce Schwann cell ingly, recent studies have suggested that remyelinating cells may ensheathment [76], and both Schwann cell proliferation and also arise from the proliferation and differentiation into mature myelination require glial ErbB2 receptors [77]. Subsequently, the oligodendrocytes of neural progenitor cells (NPCs) from germina- level of NRG1 type III expression on myelinated axons determines tive areas of the telencephalon such as the subventricular zone myelin sheath thickness [78]. (SVZ) [91,92], thus NPCs may represent an additional source of In the CNS, NRG1/ErbB signaling has been implicated in neuro- remyelinating cells in MS. Like all progenitors, OPCs and NPCs nal migration and in synaptic function [79]. In studies in vitro, are subject to precisely coordinated intrinsic and extrinsic signals NRG1 signaling also affects oligodendrocyte specification, differen- that provide highly regulated control of the balance between and J. Zhang et al. / FEBS Letters 585 (2011) 3813–3820 3817 timing of proliferation and differentiation. Manipulation of these triggered by axonal ligands including F3/ signals may facilitate expansion of the available pools of progeni- contactin has also been reported in OPC, and this pathway has been tors, and/or their subsequent differentiation into myelin-forming implicated in instructive effects on maturation [118]. Interestingly, cells. studies have also implicated Notch signaling in maintenance of the size of the NPC pool in the subventricular zone [119–121], suggest- 3.1. Bone morphogenetic proteins ing relevance to both progenitor populations that may generate remyelinating cells. 3.1.1. Role of BMPs in oligodendrocyte development Interestingly, EAE and MS lesions have been shown to display Bone morphogenetic proteins (BMPs) are a group of soluble pro- high amounts of the Notch1 receptor and its canonical ligand Jag- teins with more than 20 members, representing a major subclass of ged1, and further characterization has revealed that Jagged-1 is ex- the transforming growth factor-b (TGFb) superfamily. They are pressed by reactive astrocytes under inflammatory conditions classified into five subgroups [93]. BMP ligands bind to a complex under the influence of the cytokine TGFb1, while Notch-1 and its of the BMP receptor type 2 and Type 1 (a or b), leading to phos- downstream effector Hes5 localize to OPCs [122,123]. Notch sig- phorylation of R-Smads1, 5 and 8 and triggering their translocation naling has thus been suggested to act as a regulator of the balance to the nucleus with the co-Smad, Smad4 [94]. between differentiation and maintenance of the progenitor pool in BMPs play pivotal roles in morphogenesis from gastrulation on- demyelinating conditions. However, studies examining myelin re- wards [95]. For example, in the spinal cord, development of neuro- pair in vivo have reported contrasting findings. Initial experiments nal populations is dependent on the relative gradients of roof using PLPCreERT2:Notch1fl/fl animals did not report strong effects on plate-derived dorsal BMPs, versus the ventralizing morphogen So- remyelination [124]. Conversely, subsequent studies of lysoleci- nic hedgehog (Shh), which is expressed by the notochord and floor thin-induced demyelinating lesions in Olig1Cre:Notch112f/12f mice plate [96,97]. The same cues later control oligodendrocyte specifi- revealed mildly potentiated OPC differentiation and accelerated cation and maturation. Generation of oligodendrocyte progenitor remyelination [125]. Further complicating the field, it has also cells (OPCs) in the spinal cord occurs in two phases [98]. The first been proposed that canonical Notch signaling in OPCs may be is ventral, with OPCs observed initially within the ventricular zone countered in chronic MS lesions by the non-canonical pathway of the motor neuron progenitor (pMN) domain of neuroepithelium [126]. [99]. This requires Nkx6-regulated expression of the bHLH tran- scription factor Olig2, and occurs under the influence of Shh 3.3. Wingless (Wnt) signaling [100]. Conversely, the second phase occurs dorsally [101,102], and depends on inhibition of BMPs by the specific inhibitor Noggin In addition to extrinsic cues in lesions, progenitor maturation [103,104]. BMPs restrict Shh-induced oligodendrocyte specifica- may also be regulated by intrinsic signals. For initiation of myelina- tion [103,105] and the differentiation of specified cells [104,106] tion, immature progenitors must exit the cell cycle and differenti- (Fig. 1). Blockade of BMP signaling induces oligodendrocyte gener- ate [127], and this transition has recently been shown to involve ation both in vitro and in vivo [106,107]. epigenetic regulation, which can control cell type-specific tran- scriptional states. How these factors participate to remyelination 3.1.2. BMP expression following CNS insult in the lesioned CNS remains only partially understood, but studies Importantly, BMP expression is also upregulated following CNS have reported the involvement of histone deacetylases (HDAC) in injury or inflammation, and has been linked to glial scar formation these events [128,129]. HDAC are a class of enzymes that antago- [108–110]. BMPs are also significantly upregulated in models of nize the actions of histone acetyltransferases (HAT). Acetylation disease resulting in demyelination, suggesting relevance to myelin and deacetylation oppose each other, with acetylation functionally repair in the adult CNS [106]. For example, both lysolethicin-in- associated with active and open chromatin, whereas deacetylation duced demyelination in the spinal cord and ethidium bromide correlates with inactive, closed chromatin [130]. Interestingly, injection into the caudal cerebellar peduncle have been shown to interactions have been demonstrated between HDAC and Wingless result in upregulation of BMP4 [111,112]. Moreover, expression (Wnt) signaling, in which canonical Wnt-mediated inhibition of of BMPs 4, 6 and 7 is significantly increased in the spinal cord in OPC maturation was reversed by HDAC1 and 2 [131]. This molec- EAE, correlating with disease severity [113]. BMP4 and 5 are also ular communication within OPC appears to be important for con- both detected in MS lesions in post mortem samples [114]. Inhibi- trol of oligodendrocyte lineage commitment and differentiation tion of BMP signaling has therefore been suggested as a route to [132]. promotion of myelin repair [106]. Although still early in its trans- The transcription factor YY1 (Yin-Yang 1) is one of the mole- lational development, such a strategy may represent a future ave- cules implicated in control of the exit of OPCs from the cell cycle nue for understanding and manipulating glial responses in MS [133], and can act either as a transcriptional repressor or activator. lesions. Interestingly, conditional oligodendrocyte-specific ablation of YY1 results in impaired CNS myelination, accompanied by arrest of OPC 3.2. Canonical Notch pathway differentiation [133]. This block has been linked to loss of recruit- ment of YY1 and inhibitory HDACs to the promoters of inhibitors The Notch signaling pathway is an important regulator of the such as the Wnt transcription factor 4 (Tcf4), and the helix-loop- balance between OPC proliferation and differentiation in the devel- helix factor Id4, resulting in potent restriction of OPC maturation. oping CNS [115,116]. The Notch family includes four cell surface Relevance of these mechanisms to myelin repair has been sug- receptors (Notch1–Notch4). Following binding of the receptor to gested by the recent demonstration that Wnt–cateninb1 signaling its ligand, two cleavages, the first mediated by an ADAM metallo- is active in oligodendrocyte lineage cells surrounding MS lesions, protease and a the second by a c-secretase complex, release the and that dysregulation of Wnt signaling in OPCs results in delayed intracellular domain of the receptor (NICD) from the cell mem- myelin formation and repair [134,135]. Unexpectedly, however, brane, and it then translocates to the nucleus where it activates Tcf4-null mice display reduced rather than potentiated expression the transcription of target genes [117]. Contact-mediated activa- of oligodendrocyte terminal differentiation genes [136]. Thus, the tion of canonical Notch signaling by ligands including Jagged1 role of Wnt signaling in myelination and remyelination, and its po- and Delta1 inhibits OPC differentiation and is permissive for prolif- tential as a novel translational avenue in MS, remain incompletely eration [115,116] (Fig. 1). Conversely, activation of a non-canonical understood. 3818 J. Zhang et al. / FEBS Letters 585 (2011) 3813–3820

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