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Home , Central nervous system, Myelin, Oligodendrocyte

Ato o orsodne([email protected]) correspondence for *Author Go of University Go 37075, 3, Rein-Strasse. ioa Snaidero Nicolas glance a at Myelination GLANCE A AT SCIENCE ß 1 which neuronal of life, fine-tuning the adult for in plasticity of networks. remodeling form also a how as could serve understand explain but might to development, only us not during help may generated model is myelin This is multilayered system compacted, structure. tightly nervous a membrane central form the to we of poster, myelin around accompanying how wrapped and of model article a Glance this provide a In the in at architecture. changes of Science membrane Cell extensive axons and is shape involves along cell that process segments extension This spaced membrane system. regularly plasma nervous in a down is laid sheath myelin The ABSTRACT a lnkIsiueo xeietlMdcn,Clua ersine Hermann- , Cellular Medicine, Experimental of Institute Planck Max 04 ulse yTeCmayo ilgssLd|Junlo elSine(04 2,29–04doi:10.1242/jcs.151043 2999–3004 127, (2014) Science Cell of Journal | Ltd Biologists of Company The by Published 2014. ¨ tne,Rbr-ohSrse 0 77,Go 37075, 40, Robert-Koch-Strasse. ttingen, 1,2 ¨ tne,Germany. ttingen, n ialSimons Mikael and 2 eateto , of Department 1,2, ¨ tne,Germany. ttingen, * odc ihasedo 5msc numeiae in squid giant unmyelinated an m/sec, 25 of speed To a performances. their with comparing conduct when illustrated best are axons myelinated and unmyelinated between differences clear fundamental The is it , occupying myelin, the in that available space of amount Considering limited 1980). dry Norton, the and (50–60% (Morell component matter) main white the a , of is weight myelin In densely which comprising . matter of a white fibres, of contains is packed brain matter there the white of system, 40% the nervous around the in increase of complexity relative growing the With Introduction , Myelin, system, nervous Central Axons, WORDS: KEY n a ae fe h re od‘arw meo) eas it because (myelos), ‘marrow’ word Greek the after named was and 1982). (Ritchie, energy less times 5000 using speed same few the only of diameter of a diameter with mammalian a have must axon h em‘yln a is ondb uofVrhwi 1864, in Virchow Rudolf by coined first was ‘myelin’ term The , 0 fi,ms eo ia importance. vital of be must it, of 20% , 500 m ,weesamyelinated a whereas m, m a odc with conduct can m 2999

Journal of Cell Science oe(e ta. 02.Tu,a es ntedaee ag of range diameter the in least at Thus, size- 0.4 2012). of a al., diameter when is et a there (Lee with However, more diameters, fibres axon-mimicking of different ensheathment with axons. of dependent explain fibres together to the polystyrene cultured criteria inert sole select are the be oligodendrocytes 1972). oligodendrocytes cannot Bennett, size and that how Waxman appears it 1982; Thus, Hildebrand, and (Remahl 0.8 and yoioedoye uigteatv hs fmyelination of produced phase myelin active of estimated. the amount 2013). myelin during al., previously ( the et new oligodendrocytes of (Czopka than hours make by estimates five rate just previous zebrafish) of Thus, period faster in a during least much sheaths (at a biogenesis Oligodendrocytes its live-imaging at that recent shown Strikingly, has occurs zebrafish 1993). in myelination al., of et analysis (Pfeiffer in producers body membrane powerful our most the cells these makes which h hnbace fteoioedoye htcnettecell the connect indentify that oligodendrocytes to the was (CNS) of system branches nervous thin central the the challenge studying the axon, Schwann of the where with connection (PNS), In one-to-one a system oligodendrocytes. establish nervous cells by peripheral formed the is to contrast myelin Rio- that del revealed Pio He by Hortega brain. procedures century staining the histological a improved almost of but the neurons, marrow, later by or secreted was core, myelin that the assumed in abundant particularly is GLANCE A AT SCIENCE CELL 3000 20 reaches oligodendrocyte one of by area surface formed estimated The myelin 1978). Hahn, and Hildebrand 1980; internodes 200 80 and to 30 20 between from form ranging cortex and of callosum length internode corpus an with and layers) (or 1500 axon, lamellae large 150 single to one up around with only 1971), in myelin oligodendrocytes generate Duncan, some cord example, spinal and the For 1993). Matthews al., 1980; et 80 sheaths (Hildebrand Blakemore, myelin to thicker and and have up internodes (Murray axons longer myelinate calibre but processes larger can fewer myelinate axons, callosum that small-diameter oligodendrocytes different corpus many cells on segments) and Whereas (myelin dramatically. cortex internodes differs the the region, processes brain in the these on of Depending sheath. number myelin the with body nteCS lgdnrctsaeal omeiaeaoso a of axons myelinate 0.2 to than able larger are myelination diameter Oligodendrocytes for relationship CNS. size the strict in no is there but myelinated, 1993). fasciculus al., cuneate et become the (Hildebrand axons of myelination P20 smallest the tracts after example, whereas myelinated fibre cord, For spinal thickest are mouse the myelin. the axons within in acquire largest P1 the to at brain region, starts first the specific the of a areas always Within cortical 2008). brain some into continues in (Fields, most but especially life, in of adulthood, year (P60) young of first peak the 60 the during humans, occurs day In myelination 2001). postnatal Pham-Dinh, and and cord at (Baumann spinal regions the completed in birth almost at starts is it mice, In sequence. temporal of orders two almost by corrected be to magnitude. have 1993) al., et (Pfeiffer h imtro h xnfo o15 1500 to to 1 100 from from axon in rises the increase internode the of with diameter example, of for number the diameter, length; internodal axon between and relationship lamellae There linear 2012). a al., almost et is Chong 1971; Duncan, and (Matthews lamellae , ntePS nyaoswt imtro 1 of diameter a with axons only PNS, the In defined a in development in late relatively occurs Myelination 5000 m Rmh n idbad 90,weesclsi the in cells whereas 1990), Hildebrand, and (Remahl m m m ,bt ylntdadumeiae xn r found are axons unmyelinated and myelinated both m, m 2 ufc raprdyad10 and day per area surface m m ,btbtendaeeso 0.2 of diameters between but m, nlnt ihu o6 different 60 to up with length in m m Mra n Blakemore, and (Murray m 5 m oeue e minute) per molecules ,telnt fthe of length the m, m rmr are more or m 6 10 5 m mor m m m m 2 , utoperate must 0.2 euaemei hcns n nemdllength. they intermodal how and and thickness myelination, myelin for regulate axons select they to how oligodendrocytes myelin, how form restricted understand to have we strictly networks, neuronal CNS of the process reshapes a that activity age. as an old as into 22 regarded but of anymore be development length not mean should a with internodes , ue l,21) uigtecus feouin otmyelinated most evolution, 1997; Similar of course (Waxman, drops. the During length 2012). velocity internodal al., et conduction the Wu – for apply Chomiak g-ratios with an – considerations 1972; lower value this have Bennett, or from deviates and thickness axons higher myelin (Waxman If 2009). that 0.6 Hu, and of shown myelination. g-ratio (g- have axonal optimal optimal diameter of outer considerations index total structural the Theoretical a to as used The diameter length, is neurons. axonal ratio) in inner internodal velocity the conduction or of of for ratio thickness timing myelin, the myelin in in of changes is participates in structural form It variations subtle stimuli. a more environmental example, as that to serve possible function may that brain also appears formation It adapt sheath 2012). to al., myelin plasticity et of Mangin 2012; extent by al., the et regulated (Makinodan Liu dynamically life 2012; in adult al., is in et role and myelin development Indeed, a that during both 2008). evidence have experience (Fields, new to brain is the likely there in is neurons activity how network myelination modulating for signals, with consequences their covered functional becomes transmit axon dramatic an has whether myelin of decision the Because remodeling and plasticity Myelin n 6 aeo average P30 on between make occur intermodal that P60 shorter oligodendrocytes a much and example, with generate For but internodes, length. oligodendrocytes slightly of with number Adult-born myelin higher form new properties. al., cells et forming these different Kang and However, 2011; sheaths. oligodendrocytes al., myelin mature ( et into number Simon cells of differentiating significant 2013; time al., precursor A al., cell-cycle et a 2010). oligodendrocyte et with (Young mice days (Young all adult 40 in are sheaths virtually divide to myelin that a fact, continue forming is In oligodendrocytes there in 2013). adult-born that engaged occurs of demonstrated actively but fraction laboratory in development Richardson’s significant conducted early study D. recent biogenesis to W. a Remarkably, limited myelin adulthood. Furthermore, not experience throughout 2008). that by is (Fields, modifiable factors myelination appears environmental being various plasticity now and brain program, Pham-Dinh, it to and genetic contributes (Baumann However, process predefined developmental 2001). a a as to strictly according other. stereotypically, couple each to to neurons help these might of length activity internodal the in and/or differences synchronously, thickness of discharge axons myelin to but if possible, have example, as lengths is For maximal quickly different as velocities. there conduct conduction for brain to synchronise the only longitudinal also optimum not of neurons areas and for calculated many need a radial in their However, with speed. to conduction sheaths close developed dimensions have fibres 76 oitgaetecneto ylnpatct notefine-tuning the into plasticity myelin of concept the integrate To ylnto a entogtt cu relatively occur to been has Myelination m mto0.8 m ,weesclsta cu fe 10generate P120 after occur that cells whereas m, ora fCl cec 21)17 9930 doi:10.1242/jcs.151043 2999–3004 127, (2014) Science Cell of Journal nvivo in m ,rplieado ntutv atr naxons on factors instructive and/or repulsive m, nodrt oto myelination. control to order in , 1itroe ihalnt of length a with internodes 21 , 04% uvvsln term, long survives 30–40%) m .Tu,myelination Thus, m. , , 20– 77

Journal of Cell Science cus ug n olausfloe h oino the of 1989). motion al., et the spiralling (Bunge myelination myelin followed during the colleagues how cell and Schwann determine in Bunge To PNS a the system rather, occurs, 1954). in but, electron cells Geren, nervous derived Schwann using axon (Ben of peripheral not extension Geren, is membranous the myelin continuous Ben that examine revealed Betty chicken, of to work microscopy now-classic The Wrapping GLANCE A AT SCIENCE CELL rsre,sgetn htsm tutrsclas raeless are or (Mo used collapse is structures chemical better the when some much recognisable – that appear state areas suggesting native cytoplasmic-rich preserved, high- its its to and using sheath close by myelin architecture in – results which of Today substitution, preservation freeze 1960b). by followed Peters, freezing pressure 1960a; (Maturana, Peters, processes oligodendroglial was 1960; the it to tongues outer connected conditions, and myelin inner fixation of the in with and glial However, recognise preparation to sheath. possible sample myelin processes the of thin with progress body relatively cell its the the and connecting tissue, with the fixing architecture and accessing oligodendroglial in difficulties the to owing is PNS. wrapping spiral the of for ‘jelly model accepted crawler’) This generally ‘carpet the sheath. as known growing with (also an the which roll’ be membrane, movement. correlate underneath myelin must the moves of this not there lip continuously inner that did the follow concluded of progression motion authors to active the nuclear need process, the the wrapping would axon, as the body around However, moves edge) cell (or tongue Schwann myelin outer the If ylngot eiswt igegilpoesta,after that, internode. future process model, the glial latter encircles single the spirally a In contact, a with 2009). axonal in making begins al., or ones (‘yo-yo’ growth et motion inner myelin corkscrew myelin (Pedraza the a that in model) of or axon the top 2011), ‘serpent’ across coil al., on a as et layers twists (Sobottka new achieved manner is of thickening ‘croissant-like’ addition myelin that the suggestion 2000). the Berry, by and to average Butt led 2011; an has al., et This with Sobottka of 2009; coil al., a number et (Pedraza region 7 microscopy, the to intermodal light 5.7 CNS, an of by of periodicity the length visualised in the as along However, and, vary PNS. can layers the myelin in membrane, myelin like of moves layers much continuously generated tongue previously (Bunge inner the sheet the underneath it growing Subsequently, before the of 1961). extends internode) underneath al., 2009). moves membrane et future mode and al., (the glial turn segment et the one the makes axonal membrane (Bauer model, entire roll debate However, myelin the jelly of along motion. the the matter to a that spiralling According been accepted has a progression generally in is advances it made, were there – filled authors myelination be to of the later. appeared stages in that microscopy, processes early oligodendroglia light the between (Ioannidou in gaps time-lapse – modified Using that and observed 2012). re-adopted al., recently et myelin of was different model or patchwork biogenesis one by This from formed 1956). processes is (Luse, glial oligodendrocytes different myelin many that of suggested al., by fusion the have et forms others Robertis myelin whereas (De CNS of 1958), membranes theory, model intracytoplasmic early roll of one jelly coalescence to the According from PNS. substantially the deviate them of Some nlsso ylnwapn nteCSwslgigbehind lagging was CNS the in wrapping myelin of Analysis neti is nta nhahn otc ihteao is axon the with contact ensheathing initial first this Once proposed. been have biogenesis myelin CNS of models Several m per ln h nendldimension internodal the along appears m bu ta. 2010). al., et ¨bius ae tgso eeomn,eg oajs nendllnt othe to length internodal adjust to e.g. development, at of to Hence, oligodendrocyte. stages connected the later and of open routes transport remain biosynthetic loops myelination the after paranodal close the and growth, terminated, radial channels, is for myelinic growing radial prerequisite the a of the are fraction the for which within large Thus, a separated required Whereas loops). sheath. spatially myelin membrane paranodal are growth future of longitudinal (the pathways layer trafficking myelin each pockets membranous of cytoplasmic-rich lateral to the needs to membrane transported internode, be the of extension longitudinal the 2014). for al., are et they (Snaidero disappear completed largely that is but is in sheaths myelination overlooked myelin when collapse developing being in and for difficult found been reason mainly shrink have Another inner they to detect. tissue, the to tend dehydrated at and channels edge fixed leading chemically these the Since to membrane pathway tongue. deliver biosynthetic to contain the order myelin), in from carriers PNS vesicular of Schmidt- and the incisures microtubules of for (myelin reminiscent incisures path channels, 2011; Lanterman myelinic al., helical et These (Velumian a 2010). zone growth Nave, provide the to membrane that of transport myelin channels (myelinic) compacted appears cytoplasmic-rich There of within system sheath. elaborate myelin an developing be transported the to be through to way has the membrane all synthesised growth newly radial the for responsible myelin, is of tongue innermost advancing the If outfoldings and channels Myelinic oiina aaoa op.Drn hsltrletnin h glial and the extension, align lateral they this where During loops. node paranodal future as the position towards move edges cytoplasmic-rich 2009; These lateral 2000). Berry, al., and the Butt et 2011; to al., (Pedraza rise et Sobottka described giving previously surface, pattern axonal are helical the layer coiling with contact myelin close each in lateralalways of The regions. pockets nodal membranous the cytoplasmic-rich towards layers membrane myelin extension of lateral the the with the together underneath membrane, i.e. deposited axon, and previously the around tongue body inner the the the of at wrapping cell with edge the leading contact by grows the in myelin that width suggests model with lateral This axon. shortest contact the with direct layer innermost in the with shape layer triangular a of outermost that membrane of reveals extension flat analysis single appears a but This sheets, as membrane overlapping 2014). of serpent follow al., a not et is to myelin (Snaidero possible state to close it native volume large its made a in development has its during formation freezing, myelin high-pressure methods, as cryopreparation such with electron together scanning inner (FIB-SEM), to coupled one microscopy milling beam of membrane. ion focused of extension by layers imaging the several on of growth based lateral each not on over the but is glide generated, tongue, model and been laterally This has grow other. turns layers of membrane number individual appropriate the Once nyipratfrnd omto,btas osm xetfor extent node. some the to towards layers also myelin of but extension lateral formation, the node promoting for important only 2013; al., et Susuki 2008; al., of C et migration (Zonta retarded lateral is the layers contactin-1 myelin the or neurofascin, mice paranodal lack in Interestingly, 2008). glial, that al., et the Zonta 2009; on al., (NFASC) et (Pedraza neurofascin loops of the isoform and kDa axon, 155 the on (CNTNAP1) and contactin-associated (CNTN1) the contactin-1 of the consisting of formation complex the adhesion by axoglial axon the to attached be to appears membrane ¸olakog o h aea rwho h ylnlyr,wihi responsible is which layers, myelin the of growth lateral the For h plcto fnwtcnlge,sc ssra lc block serial as such technologies, new of application The l ta. 04.Tu,teaola deincmlxi not is complex adhesion axoglial the Thus, 2014). al., et ˘lu ora fCl cec 21)17 9930 doi:10.1242/jcs.151043 2999–3004 127, (2014) Science Cell of Journal 3001

Journal of Cell Science ifrn ylndsae nldn ymeiaigneuropathies dysmyelinating including with diseases associated frequently myelin are some different outfoldings al., that myelin et these show (Snaidero As outfoldings to 2014). myelin possible within was end channels it myelinic sheaths myelin developing of sheath. myelin the of for extension needed longitudinal membrane they for the organ, sites the delivery of preferential growth represent the may during axon the of elongation further GLANCE A AT SCIENCE CELL 3002 2 apart; layers myelin two of leaflets 3 myelin inner growing the the keeps into way spacer that myelin a One sheath deposit fibrils. to the amyloid is of nucleation within impede formation to step the site nucleation to the single similar making limiting, by a rate achieved easily is to most it is compaction This sheath, sheath. myelin limit the to in pockets crucial uncompacted of formation the lags of therefore, extension and, rapid growth the myelin with behind. up during keep tongue to innermost al., enough the et compaction the fast that Laursen not is in 2011; explanation simply al., Another et Colman is synthesised 2008). Wake 1997; al., 1987; et al., be al., White et et 2011; to (Ainger Trapp axon 1982; proposed al., the et to been close layers has innermost MBP the because at membrane local starts compaction for of that sites is site nucleation growing possibility initial One the the set. how are of compaction clear compaction not is premature It prevent compaction zone. and to the growth important myelin segregation at of are the spatial regulation in The axon coordinated starts the inward. the and compaction progresses 1987). sheath, and to al., layers myelin close outermost et the in of (Readhead occurs early region wraps starts growth innermost few and membrane a (MBP) Whereas protein only basic after bilayer myelin myelin development the by of achieved leaflets cytoplasmic is the of compaction The small Compaction and which of sheath. design in plastic myelin developing and fluid dynamic the a the enabling as freely, diffuse rather, a but, as regarded structure be of not rigid therefore, fraction should, Myelin a 1976). Gould Dawson, of that 1977; and layers (Gould, outer inwards possible spreading the before at is sheath emerging added the also It are lipids, sheath. particular in myelin edge molecules, leading growing the the at inserted that of are imply their components not membrane explain does myelin model would all This radial which life. unperturbed in itself, secure later the axon disappearance and gradual myelinated that layers the possible the of of is growth growth completion It lateral the adult. the allow to of the reservoirs membrane in as serve sheath outfoldings the that myelin of components these radial fluidity the formed close, the fully stabilise of to absence channels membrane owing the and out myelinic excess membrane spread slowly When of might outwards. accumulation outfoldings inner extends focal the that in into of channels resulting part myelinic through tongue, and membrane structure preferential of the physiological by delivery form to a seem They development. are myelin normal they sheath, that myelin mainly growing suggesting every been almost have development in appear in they outfoldings early 2004), myelin However, al., features. pathological et as Bolino regarded 2012; al. et (Pereira xed oteims aeso h ylnset Sadr tal., et (Snaidero sheath myelin the of layers inmost the to extends 2014). al., et (Snaidero function this fulfils that protein 9 cci nucleotide-3 -cyclic yuigtredmninleeto irsoyreconstructions microscopy electron three-dimensional using By opoiedrcinlt ntecmato rcs n exclude and process compaction the in directionality provide To nteasneo N,mei opcinpoed atrand faster proceeds compaction myelin CNP, of absence the In MBP RAtasain oee,ti sunlikely is this However, translation. mRNA 9 popoiseae(N)apast eone be to appears (CNP) -phosphodiesterase 9 - nraei ylntikes n xml smc nwhich in mice is example One general (3,4,5) thickness. 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GLANCE A AT SCIENCE CELL gawl . nieo . Pa N., Snaidero, S., Aggarwal, J., Zimmermann, S., Frey, C., Reetz, N., Snaidero, L., Yurlova, S., Aggarwal, References http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.151043/-/DC1. at files availableasJPEG are articleatjcs.biologists.org.Individualposterpanels ofthis version online the downloading in for available is poster the glance high-resolution of version A a at science (BMBF). Cell program (SI E-Rare Foundation Tschira-Stiftung, Research the German and the TRR43), from 10-1; grants and by 746/9-1 supported was work The Funding interests. competing no declare authors The interests Competing required cues molecular instructive are membrane their wrap vivo fibres to polystyrene able inert remarkable are around the oligodendrocytes does What that myelinated. with be finding contacts to stable need that form axons and those recognise questions oligodendrocytes unanswered how key the myelin made, is of been One incomplete. has still of progress is so picture even the aspects membrane However, may multilamellar axon. a an that key around when model stacks generated highlighted a is myelin into have how them explain incorporated we and growth review membrane this al., In et Simpson remarks Concluding 2010; al., et the are (Cotter define the can 2013). processes length axon where the both intermodal PNS, along the cells future that Schwann in of possibility demonstrated elongation as initial theoretical – the regulated There least specifically altered. that is at be growth may longitudinal is and it Finally, radial unaffected. between is ratio tongue the its inner and the channels at myelinic along production insertion transport this whereas its impaired, membrane, of of are myelin wrapping axon of the interpretation the drive myelin around that One membrane forces overall the protruding 2006). the reduced that al., is with phenotype et but (Thurnherr cytoplasm thickness of accumulation igr . vsa . in,A . ar,C,Braee .adCro,J H. J. Carson, and E. Barbarese, C., Barry, S., A. Diana, D., Avossa, K., Ainger, are iispoendfuina h elsraet eeaelpdrc myelin- -rich generate to surface cell the at sheets. diffusion limits barrier Pa 19) rnpr n oaiaineeet nmei ai rti mRNA. protein basic myelin in elements Biol. localization Cell J. and Transport (1997). al. into proteins et basic A. myelin meshwork. of I. protein transition phase Schaap, cohesive a T., a by M. driven is Weil, assembly A., membrane Schneider, A., Janshoff, h hr ls fpeoyei hti hc uainlasto mutation which in that is phenotype of class third The he,G,Jnhf,A,Fidih,J,Mu J., Friedrichs, A., Janshoff, G., ¨hler, smei,ide,ol otoldb hsclprmtr or parameters physical by controlled only indeed, myelin, Is ? 138 1077-1087. , Cdc42 e.Cell Dev. or he,G,Fe,S,Sa S., Frey, G., ¨hler, Rac1 21 LSBiol. PLoS 445-456. , noioedoye,wihresults which oligodendrocytes, in nvitro in 11 e1001577. , lr .J tal. et J. D. ller, ¨ nvivo in enfrmyelination for mean nhz . wcsetr M., Zweckstetter, P., ´nchez, hti h force the is What ? 21) size A (2011). 21) Myelin (2013). in rvl . eesn . og .W,Kti,V,Tap .adBan .E. P. Braun, and B. Trapp, V., Kottis, W., V. Yong, J., Peterson, M., Gravel, M. R. Dawson, and M. R. Gould, M. R. Gould, S., Wolfer, I., Bormuth, I., Heilmann, R., Kemper, H., J. Oltrogge, S., H. Goebbels, R. Miller, and E. G. Landreth, C., J. Karlo, L., S. Fyffe-Maricich, R. Bansal, and A. K. Nave, L., J. Dupree, M., Furusho, lrs .I,Nrynn .P,Mre .N,Sik .E,Yn . id G., Kidd, X., Yin, E., H. Shick, N., E. Morse, P., S. Narayanan, I., A. Flores, D. R. Fields, idbad . eal . eso,H n jrmr C. Bjartmar, and H. Persson, S., Remahl, C., Hildebrand, ac,S . hn .R,Brnii .E,Faki,R .adRwth .H. D. Rowitch, and J. R. Franklin, E., S. Baranzini, R., J. Chan, P., S. Fancy, F. Wald, and M. H. Gerschenfeld, E., Robertis, De iao .adDmizr .M. H. Dembitzer, and A. Hirano, R. Hahn, and C. 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