CLC number:
On-line Access: 2025-04-23
Received: 2023-10-26
Revision Accepted: 2024-02-22
Crosschecked: 2025-04-24
Cited: 0
Clicked: 1105
Qi SHAO, Simin CHEN, Tian XU, Yuyu SHI, Zijin SUN, Qingguo WANG, Xueqian WANG, Fafeng CHENG.
@article{title="
author="Qi SHAO, Simin CHEN, Tian XU, Yuyu SHI, Zijin SUN, Qingguo WANG, Xueqian WANG, Fafeng CHENG",
journal="Journal of Zhejiang University Science B",
volume="26",
number="4",
pages="303-316",
year="2025",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2300776"
}
%0 Journal Article
%T
%A Qi SHAO
%A Simin CHEN
%A Tian XU
%A Yuyu SHI
%A Zijin SUN
%A Qingguo WANG
%A Xueqian WANG
%A Fafeng CHENG
%J Journal of Zhejiang University SCIENCE B
%V 26
%N 4
%P 303-316
%@ 1673-1581
%D 2025
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2300776
TY - JOUR
T1 -
A1 - Qi SHAO
A1 - Simin CHEN
A1 - Tian XU
A1 - Yuyu SHI
A1 - Zijin SUN
A1 - Qingguo WANG
A1 - Xueqian WANG
A1 - Fafeng CHENG
J0 - Journal of Zhejiang University Science B
VL - 26
IS - 4
SP - 303
EP - 316
%@ 1673-1581
Y1 - 2025
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2300776
Abstract: myelin formation is considered the last true “invention” in the evolution of vertebrate nervous system cell structure. The rapid jumping pulse propagation achieved by myelin enables the high conduction speed that is the basis of human movement, sensation, and cognitive function. As a key structure in the brain, white matter is the gathering place of myelin. However, with age, white matter-associated functions become abnormal and a large number of myelin sheaths undergo degenerative changes, causing serious neurological and cognitive disorders. Despite the extensive time and effort invested in exploring myelination and its functions, numerous unresolved issues and challenges persist. In-depth exploration of the functional role of myelin may bring new inspiration for the treatment of central nervous system (CNS) diseases and even mental illnesses. In this study, we conducted a comprehensive examination of the structure and key molecules of the myelin in the CNS, delving into its formation process. Specifically, we propose a new hypothesis regarding the source of power for myelin expansion in which membrane compaction may serve as a driving force for myelin extension. The implications of this hypothesis could provide valuable insights into the pathophysiology of diseases involving myelin malfunction and open new avenues for therapeutic intervention in myelin-related disorders.
[1]AggarwalS,YurlovaL,SimonsM,2011.Central nervous system myelin: structure, synthesis and assembly.Trends Cell Biol,21(10):585-593.
[2]BakhtiM,SnaideroN,SchneiderD,et al.,2013.Loss of electrostatic cell-surface repulsion mediates myelin membrane adhesion and compaction in the central nervous system.Proc Natl Acad Sci USA,110(8):3143-3148.
[3]BakhtiM,AggarwalS,SimonsM,2014.Myelin architecture: zippering membranes tightly together.Cell Mol Life Sci,71(7):1265-1277.
[4]BarateiroA,BritesD,FernandesA,2016.Oligodendrocyte development and myelination in neurodevelopment: molecular mechanisms in health and disease.Curr Pharm Des,22(6):656-679.
[5]BechlerME,ByrneL,Ffrench-ConstantC,2015.CNS myelin sheath lengths are an intrinsic property of oligodendrocytes.Curr Biol,25(18):2411-2416.
[6]BifulcoM,LaezzaC,StingoS,et al.,2002.2',3'-Cyclic nucleotide 3'-phosphodiesterase: a membrane-bound, microtubule-associated protein and membrane anchor for tubulin.Proc Natl Acad Sci USA,99(4):1807-1812.
[7]BradyST,WittAS,KirkpatrickLL,et al.,1999.Formation of compact myelin is required for maturation of the axonal cytoskeleton.J Neurosci,19(17):7278-7288.
[8]CampagnoniAT,1988.Molecular biology of myelin proteins from the central nervous system.J Neurochem,51(1):1-14.
[9]ChowE,MottahedehJ,PrinsM,et al.,2005.Disrupted compaction of CNS myelin in an OSP/Claudin-11 and PLP/DM20 double knockout mouse.Mol Cell Neurosci,29(3):405-413.
[10]CoetzeeT,FujitaN,DupreeJ,et al.,1996.Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional instability.Cell,86(2):209-219.
[11]CorrealeJ,YsrraelitMC,2022.Multiple sclerosis and aging: the dynamics of demyelination and remyelination.ASN Neuro,14:17590914221118502.
[12]de FariaO,PivonkovaH,VargaB,et al.,2021.Periods of synchronized myelin changes shape brain function and plasticity.Nat Neurosci,24(11):1508-1521.
[13]DenningerAR,BreglioA,MaherasKJ,et al.,2015.Claudin-11 tight junctions in myelin are a barrier to diffusion and lack strong adhesive properties.Biophys J,109(7):1387-1397.
[14]DevauxJ,GowA,2008.Tight junctions potentiate the insulative properties of small CNS myelinated axons.J Cell Biol,183(5):909-921.
[15]EdgarJM,McLaughlinM,WernerHB,et al.,2009.Early ultrastructural defects of axons and axon‒glia junctions in mice lacking expression ofCnp1.Glia,57(16):1815-1824.
[16]EdgarJM,McGowanE,ChappleKJ,et al.,2021.Río-Hortega’s drawings revisited with fluorescent protein defines a cytoplasm-filled channel system of CNS myelin.J Anat,239(6):1241-1255.
[17]FehmiJ,SchererSS,WillisonHJ,et al.,2018.Nodes, paranodes and neuropathies.J Neurol Neurosurg Psychiatry,89(1):61-71.
[18]GargaretaVI,ReuschenbachJ,SiemsSB,et al.,2022.Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice.eLife,11:e77019.
[19]GeoffroyCG,ZhengBH,2014.Myelin-associated inhibitors in axonal growth after CNS injury.Curr Opin Neurobiol,27:31-38.
[20]GotohL,InoueK,HelmanG,et al.,2014.GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease.Mol Genet Metab,111(3):393-398.
[21]GowA,SouthwoodCM,LiJS,et al.,1999.CNS myelin and Sertoli cell tight junction strands are absent inOsp/claudin-11 null mice.Cell,99(6):649-659.
[22]GravelM,PetersonJ,YongVW,et al.,1996.Overexpression of 2',3'-cyclic nucleotide 3'-phosphodiesterase in transgenic mice alters oligodendrocyte development and produces aberrant myelination.Mol Cell Neurosci,7(6):453-466.
[23]GravelM,RobertF,KottisV,et al.,2009.2',3'-Cyclic nucleotide 3'-phosphodiesterase: a novel RNA-binding protein that inhibits protein synthesis.J Neurosci Res,87(5):1069-1079.
[24]HarauzG,IshiyamaN,HillCMD,et al.,2004.Myelin basic protein-diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis.Micron,35(7):503-542.
[25]HarryGJ,ToewsAD,1998.Myelination, dysmyelination, and demyelination. In: Slikker W Jr, Chang LW (Eds.),Handbook of Developmental Neurotoxicology.Academic Press,San Diego, p.87-115.
[26]HinesJH,RavanelliAM,SchwindtR,et al.,2015.Neuronal activity biases axon selection for myelinationinvivo.Nat Neurosci,18(5):683-689.
[27]HouAN,QuSS,FuJH,2020.Expression of connexin 47 and its effects on the myelination of oligodendrocytes in hypoxia-ischemia-induced periventricular leukomalacia in newborn rats.J China Med Univ,49(4):306-312(in Chinese).
[28]HughesEG,KangSH,FukayaM,et al.,2013.Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain.Nat Neurosci,16(6):668-676.
[29]KagawaT,IkenakaK,InoueY,et al.,1994.Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene.Neuron,13(2):427-442.
[30]KangM,YaoY,2022.Laminin regulates oligodendrocyte development and myelination.Glia,70(3):414-429.
[31]KarthigasanJ,KirschnerDA,1988.Membrane interactions are altered in myelin isolated from central and peripheral nervous system tissues.J Neurochem,51(1):228-236.
[32]KermanBE,KimHJ,PadmanabhanK,et al.,2015.Invitro myelin formation using embryonic stem cells.Development,142(12):2213-2225.
[33]KippertA,TrajkovicK,RajendranL,et al.,2007.Rho regulates membrane transport in the endocytic pathway to control plasma membrane specialization in oligodendroglial cells.J Neurosci,27(13):3560-3570.
[34]KirschnerDA,InouyeH,GanserAL,et al.,1989.Myelin membrane structure and composition correlated: a phylogenetic study.J Neurochem,53(5):1599-1609.
[35]KisterA,KisterI,2023.Overview of myelin, major myelin lipids, and myelin-associated proteins.Front Chem,10:1041961.
[36]KlugmannM,SchwabMH,PühlhoferA,et al.,1997.Assembly of CNS myelin in the absence of proteolipid protein.Neuron,18(1):59-70.
[37]KrafftPR,BaileyEL,LekicT,et al.,2012.Etiology of stroke and choice of models.Int J Stroke,7(5):398-406.
[38]KuhnS,GrittiL,CrooksD,et al.,2019.Oligodendrocytes in development, myelin generation and beyond.Cells,8(11):1424.
[39]LapatoAS,Tiwari-WoodruffSK,2018.Connexins and pannexins: at the junction of neuro-glial homeostasis & disease.J Neurosci Res,96(1):31-44.
[40]Lappe-SiefkeC,GoebbelsS,GravelM,et al.,2003.Disruption ofCnp1 uncouples oligodendroglial functions in axonal support and myelination.Nat Genet,33(3):366-374.
[41]LaursenLS,ChanCW,Ffrench-ConstantC,2011.Translation of myelin basic protein mRNA in oligodendrocytes is regulated by integrin activation and hnRNP-K.J Cell Biol,192(5):797-811.
[42]LeeJ,GravelM,ZhangRL,et al.,2005.Process outgrowth in oligodendrocytes is mediated by CNP, a novel microtubule assembly myelin protein.J Cell Biol,170(4):661-673.
[43]LeeS,LeachMK,RedmondSA,et al.,2012.A culture system to study oligodendrocyte myelination processes using engineered nanofibers.Nat Methods,9(9):917-922.
[44]LeeS,ChongSYC,TuckSJ,et al.,2013.A rapid and reproducible assay for modeling myelination by oligodendrocytes using engineered nanofibers.Nat Protoc,8(4):771-782.
[45]LepiemmeF,StouffletJ,Javier-TorrentM,et al.,2022.Oligodendrocyte precursors guide interneuron migration by unidirectional contact repulsion.Science,376(6595):eabn6204.
[46]LiuH,YangYY,XiaYG,et al.,2017.Aging of cerebral white matter.Ageing Res Rev,34:64-76.
[47]LüdersKA,NesslerS,KuschK,et al.,2019.Maintenance of high proteolipid protein level in adult central nervous system myelin is required to preserve the integrity of myelin and axons.Glia,67(4):634-649.
[48]MaglioneM,TressO,HaasB,et al.,2010.Oligodendrocytes in mouse corpus callosum are coupled via gap junction channels formed by connexin47 and connexin32.Glia,58(9):1104-1117.
[49]MathewsES,MawdsleyDJ,WalkerM,et al.,2014.Mutation of 3-hydroxy-3-methylglutaryl CoA synthase I reveals requirements for isoprenoid and cholesterol synthesis in oligodendrocyte migration arrest, axon wrapping, and myelin gene expression.J Neurosci,34(9):3402-3412.
[50]MayoralSR,EtxeberriaA,ShenYAA,et al.,2018.Initiation of CNS myelination in the optic nerve is dependent on axon caliber.Cell Rep,25(3):544-550.e3.
[51]McKerracherL,RosenKM,2015.MAG, myelin and overcoming growth inhibition in the CNS.Front Mol Neurosci,8:51.
[52]McNamaraNB,MunroDAD,Bestard-CucheN,et al.,2023.Microglia regulate central nervous system myelin growth and integrity.Nature,613(7942):120-129.
[53]MinY,KristiansenK,BoggsJM,et al.,2009.Interaction forces and adhesion of supported myelin lipid bilayers modulated by myelin basic protein.Proc Natl Acad Sci USA,106(9):3154-3159.
[54]MoscarelloMA,1997.Myelin basic protein, the “executive” molecule of the myelin membrane. In: Juurlink BHJ, Devon RM, Doucette JR, et al. (Eds.),Verge Cell Biology and Pathology of Myelin: Evolving Biological Concepts and Therapeutic Approaches.Springer,Boston, p.13-25.
[55]MüllerC,BauerNM,SchäferI,et al.,2013.Making myelin basic protein—from mRNA transport to localized translation.Front Cell Neurosci,7:169.
[56]NaveKA,2010.Myelination and support of axonal integrity by glia.Nature,468(7321):244-252.
[57]NawazS,SánchezP,SchmittS,et al.,2015.Actin filament turnover drives leading edge growth during myelin sheath formation in the central nervous system.Dev Cell,34(2):139-151.
[58]NortonWT,PodusloSE,1973.Myelination in rat brain: changes in myelin composition during brain maturation.J Neurochem,21(4):759-773.
[59]PajevicS,PlenzD,BasserPJ,et al.,2023.Oligodendrocyte-mediated myelin plasticity and its role in neural synchronization.eLife,12:e81982.
[60]PedrazaL,HuangJK,ColmanD,2009.Disposition of axonal caspr with respect to glial cell membranes: implications for the process of myelination.J Neurosci Res,87(15):3480-3491.
[61]PfeifferSE,WarringtonAE,BansalR,1993.The oligodendrocyte and its many cellular processes.Trends Cell Biol,3(6):191-197.
[62]PillaiAM,ThaxtonC,PribiskoAL,et al.,2009.Spatiotemporal ablation of myelinating glia-specificneurofascin (NfascNF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains.J Neurosci Res,87(8):1773-1793.
[63]PinatelD,Faivre-SarrailhC,2021.Assembly and function of the juxtaparanodal Kv1 complex in health and disease.Life,11(1):8.
[64]RaasakkaA,RuskamoS,KowalJ,et al.,2017.Membrane association landscape of myelin basic protein portrays formation of the myelin major dense line.Sci Rep,7:4974.
[65]RaasakkaA,RuskamoS,KowalJ,et al.,2019.Molecular structure and function of myelin protein P0 in membrane stacking.Sci Rep,9:642.
[66]RasbandMN,PelesE,2016.The nodes of Ranvier: molecular assembly and maintenance.Cold Spring Harb Perspect Biol,8(3):a020495.
[67]RoachA,TakahashiN,PravtchevaD,et al.,1985.Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in shiverer mutant mice.Cell,42(1):149-155.
[68]RosenbergSS,KellandEE,TokarE,et al.,2008.The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation.Proc Natl Acad Sci USA,105(38):14662-14667.
[69]RosenbluthJ,1980.Central myelin in the mouse mutant shiverer.J Comp Neurol,194(3):639-648.
[70]RosenbluthJ,NaveKA,MierzwaA,et al.,2006.Subtle myelin defects in PLP-null mice.Glia,54(3):172-182.
[71]RuskamoS,RaasakkaA,PedersenJS,et al.,2022.Human myelin proteolipid protein structure and lipid bilayer stacking.Cell Mol Life Sci,79(8):419.
[72]SaherG,BrüggerB,Lappe-SiefkeC,et al.,2005.High cholesterol level is essential for myelin membrane growth.Nat Neurosci,8(4):468-475.
[73]SalzerJL,ZalcB,2016.Myelination.Curr Biol,26(20):R971-R975.
[74]SargiannidouI,KimGH,KyriakoudiS,et al.,2015.A start codon CMT1X mutation associated with transient encephalomyelitis causes complete loss of Cx32.Neurogenetics,16(3):193-200.
[75]SeidlAH,2014.Regulation of conduction time along axons.Neuroscience,276:126-134.
[76]ShermanDL,TaitS,MelroseS,et al.,2005.Neurofascins are required to establish axonal domains for saltatory conduction.Neuron,48(5):737-742.
[77]SiemsSB,JahnO,HoodlessLJ,et al.,2021.Proteome profile of myelin in the zebrafish brain.Front Cell Dev Biol,9:640169.
[78]SimonsM,NaveKA,2016.Oligodendrocytes: myelination and axonal support.Cold Spring Harb Perspect Biol,8(1):a020479.
[79]SmirnovaEV,RakitinaTV,ZiganshinRH,et al.,2021.Comprehensive atlas of the myelin basic protein interaction landscape.Biomolecules,11(11):1628.
[80]SnaideroN,MöbiusW,CzopkaT,et al.,2014.Myelin membrane wrapping of CNS axons by PI(3,4,5)P3-dependent polarized growth at the inner tongue.Cell,156(1-2):277-290.
[81]SnaideroN,VelteC,MyllykoskiM,et al.,2017.Antagonistic functions of MBP and CNP establish cytosolic channels in CNS myelin.Cell Rep,18(2):314-323.
[82]SobottkaB,ZieglerU,KaechA,et al.,2011.CNS live imaging reveals a new mechanism of myelination: the liquid croissant model.Glia,59(12):1841-1849.
[83]StadelmannC,TimmlerS,Barrantes-FreerA,et al.,2019.Myelin in the central nervous system: structure, function, and pathology.Physiol Rev,99(3):1381-1431.
[84]SusukiK,ChangKJ,ZollingerDR,et al.,2013.Three mechanisms assemble central nervous system nodes of Ranvier.Neuron,78(3):469-482.
[85]SusukiK,OtaniY,RasbandMN,2016.Submembranous cytoskeletons stabilize nodes of Ranvier.Exp Neurol,283:446-451.
[86]TepavčevićV,LubetzkiC,2022.Oligodendrocyte progenitor cell recruitment and remyelination in multiple sclerosis: the more, the merrier?Brain,145(12):4178-4192.
[87]ThomasonEJ,EscalanteM,OsterhoutDJ,et al.,2020.The oligodendrocyte growth cone and its actin cytoskeleton: a fundamental element for progenitor cell migration and CNS myelination.Glia,68(7):1329-1346.
[88]TrappBD,1990.Myelin-associated glycoprotein location and potential functions.Ann N Y Acad Sci,605(1):29-43.
[89]TressO,MaglioneM,ZlomuzicaA,et al.,2011.Pathologic and phenotypic alterations in a mouse expressing a connexin47 missense mutation that causes Pelizaeus-Merzbacher-like disease in humans.PLoS Genet,7(7):e1002146.
[90]WangSQ,WangYX,ZouSQ,2022.A glance at the molecules that regulate oligodendrocyte myelination.Curr Issues Mol Biol,44(5):2194-2216.
[91]WaxmanSG,BennettMVL,1972.Relative conduction velocities of small myelinated and non-myelinated fibres in the central nervous system.Nat New Biol,238(85):217-219.
[92]WeimbsT,StoffelW,1992.Proteolipid protein (PLP) of CNS myelin: positions of free, disulfide-bonded, and fatty acid thioester-linked cysteine residues and implications for the membrane topology of PLP.Biochemistry,31(49):12289-12296.
[93]ZalcB,GoujetD,ColmanD,2008.The origin of the myelination program in vertebrates.Curr Biol,18(12):R511-R512.
[94]ZucheroJB,FuMM,SloanSA,et al.,2015.CNS myelin wrapping is driven by actin disassembly.Dev Cell,34(2):152-167.
Open peer comments: Debate/Discuss/Question/Opinion
<1>